Drug resistance in pathogenic microorganisms may be intrinsic or acquired. Foreign-resistant genes can be introduced into the recipient organism by transformation, transduction, or conjugation to confer resistance (43).

Mutations at many chromosomal locations cause this AMR and can take the following forms: i) spontaneous mutations: this type of mutation often occurs in actively dividing cells, thus the name growth-dependent mutations (43). They arise as random replication mistakes or improper DNA damage repair (43); (ii) hypermutators: these are highly mutable bacteria, and their hypermutable condition results from prolonged exposure to sublethal antibiotic dosages. These cells can escape the hypermutable stage if they acquire a beneficial mutation and begin to divide and multiply (44); and (iii) adaptive mutagenesis: this mutation happens in slow-growing cells exposed to sublethal antibiotic dosages (43).

Horizontal gene transfer allows microorganisms to acquire antibiotic resistance genes from unrelated organisms. This transfer occurs primarily through transformation, transduction, and conjugation. Recombination, a separate process, can also introduce or modify resistance genes within a recipient’s genome (44).

Phenotypic drug resistance, occurring without genetic changes, arises from a microorganism’s physiological state and its inherent survival strategies (45). This resistance can manifest through various mechanisms, including drug indifference, biofilm formation, persistence, inoculum size effects, and metabolic-state-dependent alterations in antibiotic susceptibility (45).

Susceptibility to antimicrobial agents can vary depending on an organism’s physiological state (46). For instance, dormant cells have demonstrated resistance to ampicillin and tetracycline, whereas rapidly dividing cells are more vulnerable. Conversely, while not actively growing, stationary-phase cells are susceptible to ciprofloxacin and streptomycin (46).

The punctate age of dormant cells reveals the occurrence in an antibiotic-resistant microbial culture (47). Persistence comes in two different varieties: Type I and Type II. The first kind is induced by cellular deprivation, whereas the second arises due to the developing cells’ innate biostability (48).

Biofilm development results from attaching free-living (planktonic) cells to surfaces, as detailed below (49): (i) it involves attaching free-living cells to a pre-conditioned surface by random propulsion, chemotaxis, or motion (49). The initial cell attachment is often reversible and is influenced by various physical and chemical variables (50); (ii) The production of adhesion proteins, such as fimbriae, helps in the permanent attachment of the cells. In addition, internal linkages and extracellular polymeric substances (EPS) emerge after cell adhesion (51). The EPS is formed of polysaccharides, such as colonic acid, chitosan, and alginate, typically generated by the microbial cells and serves as a covering for the sessile cells. Some enzymes, RNA, DNA, nutrients, proteins, and surfactants are additional EPS components (51).

During this stage, the biofilm community experiences microbial proliferation and communication using chemical signaling, leading to micro-colonies growth (52). The biofilm’s resistance to some antimicrobials results from its capacity to impede the antibiotics’ penetration via the EPS layer. For example, Pseudomonas aeruginosa biofilms are resistant to aminoglycosides (often positively charged) due to the organisms’ alginate secretion, which binds to the positively charged antibiotic (53).

The efficacy of antibiotic treatment is supposedly affected by inoculum size (54). The elevated importance of the infectious dose of microorganisms in vivo may elucidate the disparity between an antibiotic agent’s minimum inhibitory concentration (MIC) in vitro and in vivo (54). An increased quantity of bacteria that generate enzymes capable of degrading drugs correlates with an escalation in the degradation of medications. The consequence for species devoid of these degrading enzymes remains uncertain (54).

Two factors cause the AMR in these bacteria: (i) a drop in drug concentration resulting from the existence of supplementary drug target sites in both viable and non-viable cells, and (ii) an inadequate ratio of medicinal compounds to a high concentration of microorganisms (55). Based on experimental and mathematical models, both outcomes could apply to drug resistance depending on the size of the inoculums (56).

Enterococci are facultative anaerobes, ovoid (0.5–1 µm in diameter), stationary, and non-sporulating, Gram-positive cocci generally regarded as common human commensals (67). They are exceptionally adapted to prosper in nutrient-rich environments that are deficient in oxygen, such as the diverse ecosystems present in the oral cavity, gastrointestinal tract, and vaginal canal (68). The typical quantity of bacterial cells excreted is roughly 10¹¹ per gram of feces. They predominantly constitute the commensal gut microflora (69).

Although there are over 40 physiologically unique species of Enterococcus, only two species account for over 90% of enterococci infections: E. faecalis, and E. faecium (67). Infrequently, enterococci induce infections in healthy and consistent hosts. Endocarditis, sepsis, surgical wound illnesses, urinary system diseases, secondary bacteremia, and inflammatory bowel diseases are among the nosocomial ailments to which E. faecalis is reportedly becoming a significant contributor, according to surveillance data (70).

Enterococci species’ pathogenicity is determined by several characteristics, such as their typical habitat of the gut, how easily they increase there, the ability to detect a range of extracellular matrix proteins, and the availability of collecting material (71). Enterococci rely on biofilm formation to facilitate the development of endodontic and urinary system infections and endocarditis. Sortase C gene, EBPa, EBPb, and EBPc are the components of endocarditis and biofilm-associated pili (EBP) (72). E. faecalis secretes virulence factors that actively suppress host immune responses, including the production of toxins such as cytolysin and extracellular enzymes (73). Antibiotic resistance in enterococci increases the likelihood of colonization and infection and is directly associated with the therapeutic importance of the bacteria. All enterococci have reduced sensitivity to ampicillin, cephalosporins, penicillin, and all semisynthetic penicillins due to the production of penicillin-binding proteins with poor affinity (73).

One of this adaptation’s most obvious effects is the emergence of the genes that cause glycopeptide-vancomycin resistance (74). During the 1960s, MRSA emerged and spread in correlation with the use of vancomycin (74). Conversely, unlike MRSA, enterococci can assemble and sustain a range of gene clusters encoding the metabolic apparatus required for vancomycin resistance (74). Antibiotic-resistant enterococci can transfer their resistance to other pathogens, such as S. aureus and antibiotic-susceptible enterococci, by pheromone-mediated conjugative plasmids or transposons. This significantly threatens public health (74).

Recombinant transmission of dynamic genetic components requires interaction between the donor and recipient cells (74). The interaction occurs inside the microbial biofilm and is encouraged by the release of bacterial sex pheromones, which are small peptides that induce a sexual response and lead to the aggregation or clustering of cells (74). Up to 90% of human enterococcal infections are caused by E. faecalis, which also ranks third among hospital-acquired diseases brought on by resistant bacteria. For these reasons, E. faecalis is a serious hazard to human health (74).

S. aureus is a Gram-positive nonmotile bacterium which does not produce spores. The diameter of S. aureus ranges from 0.5 to 1.5 µm (75). It constitutes a component of the standard microbial population within the human body, namely in the anterior region of the nostrils, and has the potential to induce infections in individuals with compromised immune systems (75). Approximately 30% of individuals are permanent carriers of this bacterium. S. aureus has a resilient, somewhat amorphous protective coating measuring 20–40 nm in thickness on its cell wall (76). Peptidoglycan, constituting 50% of the staphylococci’s mass, is crucial for forming the thick, multilayered structure of the cell wall and sustaining the elevated intracellular osmotic pressure of the bacterium (77, 78).

When the host’s immune systems are compromised, colonization increases the probability of infection as the pathogen becomes virulent (79, 80). S. aureus is a significant contributor to both hospital-acquired and community-acquired infections, which can result in serious consequences if not addressed. The excessive use of antibiotics intensifies this organism’s resistance to drugs (81, 82).

S. aureus infects by breaching the integrity of the skin or mucous membranes, disseminating locally or systemically to distant organs, leading to severe and life-threatening invasive infections, including bloodstream infections, pneumonia, systemic infections, joint infections, and osteomyelitis (83). It also induces toxin-mediated illnesses when ingested through contaminated food. Food poisoning, and toxic shock are toxin-mediated illnesses caused by S. aureus (84, 85). In certain circumstances, exposure to secretions such as saliva or aerosols emitted during sneezing or coughing may facilitate disease transmission. This bacterium may also be present in unpasteurized milk and other animal products (86).

Pigs, cattle, and poultry may contract S. aureus, resulting in mastitis, arthritis, septicemia, and other conditions (87). The virulence factors of S. aureus are defined by their mechanisms of invasion and proliferation, production of extracellular substances, toxins, and capacity to form biofilms (88, 89). Infection pathogenesis often commences with cellular attachment, succeeded by bacterial invasion and colonization of host tissue. This process releases many adhesion proteins, including elements of the microbial surface that recognize sticky matrix molecules (90, 91).

In contrast to virulence proteins associated with the cell wall, the secreted virulence factors of S. aureus aggressively undermine human defenses by causing harm to host cells and tissues (91). They also impair the host’s immune response by releasing nutrients and promoting the dissemination of pathogens (92). Released virulence factors are classified into four primary categories: superantigens, diverse exoenzymes, random proteins, and pore-forming toxins (88, 93).

Research has shown that staphylococci can acquire resistance to antibiotics such as erythromycin, ampicillin, tetracycline, methicillin, and vancomycin (94). The van gene confers resistance to vancomycin, likely resulting from gene transfer between S. aureus and vancomycin-resistant enterococci (94). The swift global proliferation of methicillin- and vancomycin-resistant S. aureus strains is rendering containment increasingly unfeasible, potentially reverting us to the pre-antibiotic era (94). In regions with minimal methicillin resistance, penicillin, β-lactam antibiotics, cephalosporins, and clindamycin continue to be effective in treating S. aureus infections (95). The utilization of non-lactam antibiotics for the treatment of S. aureus infections has markedly increased owing to the emergence of antibiotic-resistant bacteria, especially MRSA (96).

Methicillin resistance in S. aureus developed swiftly in 1961, within two years after the drug’s clinical launch (97). This bacterium is intrinsically vulnerable to β-lactam agents that impede cell wall synthesis by binding to proteins implicated in peptidoglycan assembly (98). MRSA exhibits resistance to β-lactam antibiotics, including methicillin, isoxazolyl penicillin, and cephalosporins, by modifying its target site. The modification is achieved through the acquisition of penicillin-binding protein 2a, produced by the mecA gene (99). Nosocomial infections, including MRSA, have been acknowledged for numerous years (100). This bacterium can colonize and establish biofilms on biomaterials, leading to a significant prevalence of hospital-acquired infections referred to as HA-MRSA. HA-MRSA is a kind of MRSA infection identified when a positive culture is obtained more than 48 h after a patient’s hospital admission. This infection is managed in a hospital environment (21).

Community-acquired MRSA refers to the transmission of MRSA to the broader community. Various populations, including athletes, inmates, prospective military personnel, nursery attendees, injectable drug users, those often exchanging contaminated commodities, and residents of densely populated areas, have been associated with community-acquired MRSA epidemics (101, 102). Individuals with MRSA who come into contact with animals may transmit the bacterium, leading to livestock-associated infections (LA-MRSA). LA-MRSA has been identified in many animal species (103).

S. epidermidis, a member of the human body’s normal flora, is frequently isolated from various epithelia, including the nose, axillae, and head (104). This organism normally has a symbiotic relationship with its host and prevents pathogenic microorganisms from invading the host (105). Because of its exploitative qualities, particularly in nosocomial infections in immunocompromised patients, the medical community is very interested in controlling this disease (106). Infections produced by coagulase-negative S. epidermidis, possibly related to its proclivity to build biofilms, are prevalent in patients with implanted medical devices (107).

S. epidermidis infections can be caused by normal skin flora at the insertion site, contaminated medical equipment prior to implantation, or healthcare professionals (108). It has also been proposed that these infections were caused by long-term hospitalizations, surgical procedures after implantation, infections in neighboring tissues, and tissue damage following implantation operations (108, 109). Methicillin, one of the principal treatments for Staphylococcus species infections, is resistant to 75-90% of S. epidermidis strains obtained from hospital specimens (110). This bacterium has several antibiotic-resistant forms, including tetracycline, chloramphenicol, erythromycin, sulfonamides, fluoroquinolones, clindamycin, and rifamycin (111).

L. monocytogenes is a bacterium that causes illness and belongs to the Gram-positive bacteria found in wet environments such as soil, water, and rotting plants and animals (112). It may thrive with refrigeration and other food preservation techniques. People who consume L. monocytogenes-contaminated food may get listeriosis. L. monocytogenes is commonly transmitted through contaminated food processing (112). The symptoms of the condition might persist anywhere from a few days to many weeks, depending on its severity. Fever, muscle cramps, vomiting, diarrhea, and nausea are examples of minor symptoms (112). The most severe form of listeriosis is characterized by headaches, stiff neck, disorientation, loss of balance, and convulsions. Listeriosis can kill infants, the elderly, and immunocompromised people (112, 113).

E. coli, a Gram-negative, rod-shaped, facultatively anaerobic coliform bacterium, is frequently found in the lower intestines of warm-blooded mammals (114). The majority of E. coli strains are typical residents of the gastrointestinal tracts of humans and animals. Furthermore, it was demonstrated that E. coli cells penetrate the neonatal digestive tract immediately after birth (115). The disease-causing groups are classified into two categories: one responsible for intestinal problems and another for infections beyond the intestines, such as sepsis and bladder infections (116).

E. coli is characterized by a diverse array of harmful genotypes, categorized as pathotypes based on their ability to cause disease. Entero-toxigenic E. coli (ETEC) strains have been identified in neonates experiencing diarrhea in developing countries, and they are responsible for secretory diarrheal infections in animals (117). Two serotypes of enteropathogenic E. coli (EPEC) are present: O55:H6 and O127:H6, with atypical strains inducing diarrhea in developed nations. Conversely, the majority of prevalent strains are obtained by fecal contamination (118). Enterohemorrhagic E. coli (EHEC) strains are associated with foodborne infections commonly acquired by the consumption of milk and inadequately cooked animal products, particularly meat (118). Two distinct kinds of Shiga-like toxin producers are found in this group: stx1 and stx2 (119). Entero-invasive E. coli (EIEC) have comparable biochemical, genetic, and pathogenic properties with Shigella species and are known to cause various human diseases (119). Colitis and watery diarrhea are the most common diseases EIEC causes; these infections differ from those brought on by other strains of the same bacteria (119).

Another variant of E. coli is referred to as diffusely adherent E. coli (DAEC) strains. These strains are characterized by the diffusely adherent pattern noted in the HEp-2 adherence assay and are implicated in the etiology of watery diarrhea syndrome in adults (120). Enteroaggregative E. coli (EAEC) is a strain characterized by its remarkable adhesion to HEp-2 cells in culture. They are associated with chronic diarrhea, notably in underprivileged nations and the developed world, particularly among those with HIV/AIDS (120). Human extra-intestinal infections may also be induced by E. coli pathotypes linked to sepsis, meningitis, urinary tract infections, and bloodstream infections. E. coli O18:K1:H7 can cause invasive infections in newborns and urinary tract problems. Certain E. coli strains exhibit resistance to carbapenems, β-lactams, and various other pharmaceuticals (120).

It is a Gram-negative bacterium that commonly inhabits human lips, skin, and intestines, and has been associated with nosocomial infections. Certain illnesses, such as cancer, diabetes mellitus, liver and biliary tract conditions, and alcoholism, impair the immune system, heightening vulnerability to K. pneumoniae infections (121). This bacterium is also known to cause pneumonia, urinary tract infections, skin infections, and open wounds (121).

Klebsiella infections are frequently managed with cephalosporins, either alone or in conjunction with aminoglycosides (122). Nonetheless, the extensive administration of powerful antibiotics in individuals with Klebsiella infections has resulted in the emergence of drug-resistant bacteria, especially those that produce extended-spectrum beta-lactamase (ESBL) (123). Carbapenems can adversely affect ESBL producers; however, these organisms have evolved novel enzymes known as K. pneumoniae carbapenemases (KPCs) that can degrade carbapenems and have disseminated globally (124, 125). No advancements have been made in synthetic or natural antimicrobials, hence ESBL-producing bacteria remain a significant danger. Bacteria that produce ESBL exhibit increasing resistance to antibiotics, including fluoroquinolones, aminoglycosides, tetracyclines, trimethoprim/sulfamethoxazole, and chloramphenicol (126).

It is a potentially pathogenic Gram-negative, rod-shaped, spore-forming, and monotrichous bacterium found in aquatic environments and soil surfaces. It possesses an iridescent appearance and emits an aroma reminiscent of grapes or tortillas (127). It exhibits optimal growth within the temperature range of 25°C to 37°C, and its ability to flourish at 42°C sets it apart from numerous other Pseudomonas species. P. aeruginosa is a ubiquitous bacterium capable of persisting in various ecological environments (127).

The bacterium’s intrinsic antibiotic resistance is a significant characteristic that enables its survival under many extreme environmental conditions, both natural and artificial, including biofilms in healthcare settings. This bacterium induces nosocomial infections, especially in immunocompromised persons with neutropenia, severe burns, and cystic fibrosis (128).

Pathogenic P. aeruginosa can cause external and internal infections, including wounds, urinary tract infections, pneumonia, eye infections, sepsis, and endocarditis (129). A surge in MDR Pseudomonas infections has been seen, irrespective of the combination therapy employed (130). The pathogens inflict significant damage to host tissue by cleaving immunoglobulin G and A, modifying the cytoskeletal structure, and disintegrating actin filaments. Specifically, exotoxins, proteases, and exoenzymes, this mechanism facilitates the invasion, spread, and advancement of chronic infections (131).

P. aeruginosa poses a significant challenge in the medical domain for the treatment of infections acquired in hospital environments and the population (132). This bacterium can acquire resistance genes by horizontal gene transfer to aminoglycoside-modifying enzymes and extended-spectrum β-lactamases (132). Resistance may also emerge from modifications in chromosomal genes located at the efflux and target sites, and pathogenic isolates of this or related species have been documented to exhibit antibiotic resistance by innate, acquired, and adaptive mechanisms (132). P. aeruginosa exhibits resistance to several antibiotics, including cephalosporins, carbapenems, aminoglycosides, quinines, ureidopenicillins, quinolones, cefepimes, penicillin, and polymyxins (133, 134).

Salmonella species, such as Salmonella enterica serovar Typhimurium, Typhi, and Enteritidis, are worldwide dispersed Gram-negative bacteria recognized as significant contributors to several human diseases (135). Salmonella can be disseminated through multiple vectors, including contaminated food and water, human and animal excrement, and deceased animals. Also, S. enterica serovar Typhimurium can be obtained from numerous infected foods, including beef and pig products (136).

Salmonellosis is also linked to contaminated fresh fruits and vegetables, including apples, cantaloupe, alfalfa sprouts, mangoes, lettuce, cilantro, unpasteurized orange juice, tomatoes, melons, celery, and parsley (137). Poultry products, such as chickens, turkeys, geese, and ducks, have been associated with the transmission of Salmonella infections. Salmonella exhibiting resistance to ampicillin, chloramphenicol, and trimethoprim-sulfamethoxazole have been detected in multiple regions, particularly S. enterica serovar Typhimurium (138).

Shigella is a bacterium classified under the Enterobacteriaceae family. It is distinguished by its Gram-negative characteristics, absence of capsules, and lack of motility (139). S. flexneri is one of the four species of this genus commonly associated with bacillary diarrhea, the principal clinical manifestation of shigellosis, characterized by inflammation of the colon. The symptoms may range from asymptomatic carriage to diarrhea and dysentery (139).

Shigella can reside in humans and captive monkeys, and it is estimated that fewer than 200 bacterial cells are sufficient to induce an infection. Consequently, the proliferation of the bacteria is more probable in highly populated regions with inadequate sanitation, and annual Shigella outbreaks are anticipated to surpass 150 million cases (140). Shigellosis predominantly affects children in developing nations, who are the most severely harmed. Conversely, the epidemic is widespread in congested establishments inside affluent countries, including daycare centers, correctional facilities, and military recruitment camps (141).

Despite the manageable prevalence of shigellosis infections due to the availability of several antibiotic regimens, the emergence of drug-resistant strains is alarming. Antibiotics such sulfonamides, tetracycline, ampicillin, and chloramphenicol are ineffective against these pathogens (141).

Identifying appropriate treatment for fungal infections without harming the host is the most difficult aspect. This is attributable to the physiological cellular similarities between fungi and humans. Consequently, effective therapies for fungal infections are limited in comparison to those for bacterial disorders (111). Mycoses have become a notable concern in modern medicine owing to the rising population of patients receiving immunosuppressive treatment or experiencing immunodeficiency (142).

Candida species generally exist as unicellular yeasts in a symbiotic connection with their human hosts (143). These yeasts are often confined to the skin, gastrointestinal tract, reproductive organs, and mucosal surfaces of the oral cavity. C. albicans can alternate between two unique forms: a unicellular yeast that reproduces via budding and can also produce elongated filaments, comprising pseudomycelium (143). This capability is essential in infections where the invasive hyphae can disseminate throughout the affected tissue or organ (143).

In contrast, yeast cells disseminate to many regions. This commensal yeast is classified within the genus Candida and is typically located in the oral cavity, dermis, gastrointestinal tract, and vaginal canal of females (144). C. albicans demonstrates a growth pattern marked by yeast cells that are spherical to oval, measuring 3 to 5 µm in width and 5 to 10 µm in length (145).

C. albicans often exists as a nonpathogenic commensal organism. Nonetheless, an excessive presence of this yeast may create a perilous scenario as it can inhabit almost all human tissues and provoke severe systemic infections in individuals with compromised immune systems (146). C. albicans is the sixth most prevalent pathogen in the bloodstream for both acute and chronic yeast infections in humans and is a recognized source of nosocomial infections, particularly in immunocompromised individuals (147).

HIV infection and diabetes are two comorbid conditions frequently linked to this yeast. It is well acknowledged as the etiology of vulvovaginal and oropharyngeal candidiasis. Oral candidiasis, vulvovaginal candidiasis, and invasive candidiasis are illnesses resulting from Candida infections. Oral candidiasis is an opportunistic infection of the oral cavity. It is prevalent among elderly individuals, especially those who utilize dentures (148). This disease is typically transferred to immunocompromised individuals and may signify systemic diseases such as diabetes (149).

In women of reproductive age, particularly those who are HIV-positive, C. albicans is responsible for the heightened prevalence of vulvovaginal candidiasis (150). Nosocomial infections may result from invasive candidiasis, or candidemia, which is the most prevalent opportunistic mycosis worldwide (151). Invasive nosocomial infections can present as urinary tract infections, surgical site infections, bloodstream infections (fungemia), catheter-associated skin abscesses, and myocarditis (152).

C. albicans possesses several acknowledged virulence factors implicated in disease. C. albicans virulence factors bind to endothelial cells in blood vessels and epithelial cells in the respiratory tract, thereby greatly influencing pseudo-hyphae development (152). Surface recognition molecules, hyphal switching, and phenotypic switching facilitate this process. Extracellular hydrolytic enzymes are crucial for the dissemination of microorganisms since they facilitate adhesion, tissue infiltration, invasion, and ultimately, the destruction of host tissue (152).

A common virulence factor that facilitates sickness is hemolysin. Hemolysin-induced erythrocyte lysis enhances iron absorption, an essential component for yeast growth and pathogenic functions (153). Candida lysin contributes to immunological activation, phagocyte recruitment, tissue invasion, and epithelial injury (154, 155).

The azole class is the most often used antifungal for the treatment of Candida infections (156). They are preferred for managing various Candida infections due to their cost-effectiveness, less toxicity, and simple oral administration (156). Currently, there are four primary kinds of antifungal agents utilized for the treatment of severe mycoses, classified according to their mode of action (1): Amphotericin B modifies cell membrane functionality (2); Flucytosine obstructs DNA or RNA synthesis (3); Azoles, including fluconazole, itraconazole, voriconazole, posaconazole, and ravuconazole, impede ergosterol production; and (4) Echinocandins, such as caspofungin, micafungin, and anidulafungin, inhibit glucan synthesis (156, 157).

Over the past decade, there has been a notable rise in the incidence of drug-resistant fungal infections among hospitalized patients. The rise is particularly pronounced with frequently utilized antifungal agents, including fluconazole, miconazole, clotrimazole, tioconazole, amphotericin B, and echinocandins (158). Antifungal resistance mechanisms can be classified into three primary categories: (1) modified drug targets, (2) diminished effective drug concentration, and (3) metabolic bypasses (156).

There are fewer pharmacological options for treating Candida infections compared to bacterial or viral infections, and incidences of treatment resistance are more prevalent (159). The initial report of C. albicans strains exhibiting resistance to azole antifungals occurred in the late 1980s. Since its discovery in the 1990s, fluconazole has been the preferred antifungal agent for unicellular and multicellular fungal infections (159). Nonetheless, despite its initial effectiveness within the medical community, significant instances of medication resistance have arisen, notably among those who are HIV-positive (160).

C. tropicalis, a species separate from C. albicans. Non-C. albicans Candida (NCAC) is recognized for its ability to induce oral infections (161). The incidence of nosocomial infections, specifically NCAC infections, can be ascribed to several medical interventions and situations, including cancer treatments, surgical implantations, HIV, AIDS, and the overuse of antibiotics (161, 162). C. tropicalis is the most pathogenic among the NCAC species due to its capacity to bind and release proteinases. It is one of the most significant invasive features of pathogenic organisms towards epithelial cells (163). It inhabits the mouth cavity and skin and has been associated with esophageal and nosocomial infections (163).

Candida strains can form biofilms on medical equipment, making them resistant to antifungal agents (164). The incidence of illnesses attributed to C. tropicalis is rising globally, designating this organism as a notable emerging pathogenic yeast. The cause of this organism’s dominance over other NCAC species and its fluconazole resistance remains unidentified (165).

Bioactive components in plant extracts can be isolated, identified, and evaluated by high-performance liquid chromatography (HPLC) (176). HPLC can be classified into two primary categories: analytical HPLC and preparative HPLC (176). Analytical HPLC primarily assesses the qualitative and quantitative characteristics of a given component. Conversely, preparative HPLC is dedicated to the extraction and purification of a valuable chemical (176). The preparative HPLC method is extensively employed to identify physiologically active chemicals (176).

Mass spectrometry (MS) and nuclear magnetic resonance (NMR) are frequently employed to detect pure substances. MS is a scientific method that use ionization and separation to examine ions according to their mass-to-charge ratio. The mass-to-charge ratio serves as the independent variable for plotting the ion signal in a mass spectrum (176). The elemental or isotopic characteristics of a sample, the masses of particles and molecules, and the chemical structures of molecules can all be determined by MS (176). NMR can accurately detect the chemical features of compounds, including the quantities of carbon and proton atoms, bonding patterns, molecular geometries, and relative and absolute stereochemistry’s (176).

Gas chromatography and mass spectrometry (GC–MS) can be employed to analyze essential oils. This device employs an inert gas stream to introduce the sample into the mobile phase (177). The vaporized sample is upheld by inert material while it traverses the stationary phase of the capillary column. The specific analytes/compounds are transmitted through a MS detector, and the resultant data is presented on a computer or recording apparatus (177).

Utilizing an ethnopharmacological strategy for the screening of bioactive components provides multiple advantages (176). It facilitates the pre-screening of gathered species according to their ethnomedicinal applications and preliminary safety standards, so substantially reducing the time and cost of the process (176, 177). Numerous natural compounds derived from medicinal plants have been effectively identified by the ethnopharmacological method, and these compounds have provided a foundation for innovative methods in the pharmaceutical sector. An example of this is the method employed to extract artemisinin, an antimalarial compound, from the plant A. annua (177).

The bioactive components of various medicinal plants against certain MDR microorganisms are illustrated in Table 1 , which demonstrates their effectiveness against specific MDR microorganisms. Furthermore, examples of primary and secondary metabolites found in medicinal plants are presented in Figure 4 .

Medicinal herbs include many active compounds, whether fresh, dried, or crushed. These constitute the essential principles of phytotherapy. Conversely, the majority of conventional pharmaceutical drugs, including those with components derived from medicinal plants, function as a chemical marker with a singular active ingredient (201). Cinnamon exemplifies these two processes effectively. Historically, infectious diseases were treated with an infusion of cinnamon bark. The primary secondary metabolite of the bark, cinnamaldehyde, demonstrated efficacy as an antibacterial agent and may serve as a traditional remedy comparable to synthetic antimicrobials (201).

About 67% of anti-cancer pharmaceuticals comprise chemicals derived from or primarily produced from flora or fauna (201). Many are employed in the treatment of cancer, particularly as chemotherapeutics. The FDA has included taxol (Paclitaxel), a phenolic chemical sourced from the bark of Taxus brevifolia, in its roster of authorized cancer medications (201). Moreover, several extracts are available as commercially sold goods. Xuancheng Baicao Plants Industry and Trade Ltd., situated in China, offers powdered Lonicera (honeysuckles) extract containing 25% chlorogenic acid and Ganoderma extract with a 30% polysaccharide content (202).

The efficacy of solvents employed to extract active compounds from medicinal plants varies. Moreover, preparations of medicinal plants and essential oils exhibit significant antioxidant and antiviral activities. Clove extract exhibits superior antioxidant action compared to vitamin C against 2,2-diphenyl-1-picrylhydrazyl (DPPH), 2,2′-casino-bis (3-ethylbenzothiazole-6-sulfonic acid) (ABTS), and superoxide radicals. Moreover, clove extract and essential oil have antiviral properties (202). The chemical composition of medicinal plants, especially the occurrence of phenolic compounds, is linked to their notable antioxidant and antibacterial properties in extracts and essential oils (113).

Before the discovery of microorganisms and their functions, humanity has traditionally recognized plants as a source of medical efficacy (202, 203). Medicinal plants are effective against various viruses, including herpes, adenovirus, poliovirus, and coxsackievirus, and possess anticancer and anti-inflammatory properties (203). In light of the increasing use of herbal therapy as an alternative to traditional antibiotics and the proliferation of antibiotic-resistant bacteria, numerous studies have been conducted on the antibacterial properties of medicinal herbs (204, 205). These medicinal plants are acknowledged to possess significant untapped bioactive chemical potential (205–208).

Numerous therapeutic plant extracts possess secondary metabolites exhibiting significant efficacy against MDR microorganisms. Panda et al. (209) demonstrated a range of ethnobotanical plants possessing MDR characteristics. The acetone extract of the leaves of Smilax zeylanica and Syzygium praecox, known for their efficacy in treating ulcers and skin infections, showed antibacterial activity against MRSA by compromising cellular membranes via ionic and electrostatic interactions (209). Moreover, the ethanol extract of long-leaf varnish tree fruit exhibits MDR activity against E. faecium, S. aureus, K. pneumoniae, A. baumannii, P. aeruginosa, and Enterobacter species via ionic interactions between terpenoids and steroid compounds in the extract and the bacterial cell membrane (209).

The ethanol extract of climbing acacia leaves is utilized ethnobotanically to alleviate dysentery and diarrhea, as well as to reduce cholesterol levels, whilst the acetone extract of java cedar leaves is employed to address skin ailments. The antimicrobial activity of both plants against K. pneumoniae, A. baumannii, P. aeruginosa, and Enterobacter species is attributed to electrostatic interactions between positively charged secondary metabolites and negatively charged bacterial cell membranes. The amphipathic properties of Ceylon olive blossom aqua extract, Buddha coconut bark ethanol extract, and charcoal tree leaves acetone extract facilitate concurrent interaction with MDR bacterial cells, including K. pneumoniae, A. baumannii, P. aeruginosa, and Enterobacter species (209). Furthermore, the extracts employed in traditional medicine for the treatment of cardiovascular diseases, dermatological infections, and wound infections (209).

Richwagen et al. (210) indicated that the ethanol extract of lavender woody stems may alleviate pain through ionic interactions between the cell membranes of MDR S. aureus, A. baumannii, and P. aeruginosa and the flavonoid extract. The methanol extract of coastal golden leaf and bark is traditionally recognized for its efficacy in addressing digestive disorders, ocular issues, and infertility, exhibiting hepatoprotective, antioxidant, anticancer, antiviral, and antibacterial attributes (210). The amphipathic characteristics of the plant contribute to its antibacterial efficacy against MDR S. aureus, K. pneumoniae, P. aeruginosa, Enterobacter species, and MRSA (210).

Pallah et al. (211) demonstrated a range of plants exhibiting MDR activities. Cherry plum, plum, red currant, and methanol extracts exhibited antioxidant, anti-inflammatory, and antibacterial activities against MDR species, including S. aureus, K. pneumoniae, and P. aeruginosa, through electrostatic interactions (211). The Jostaberry methanol extract demonstrated inhibitory zones against S. aureus and P. aeruginosa using the same method (211). Additionally, methanol extract of sweet cherry fruit is conventionally employed to alleviate osteoarthritis and address cardiovascular illnesses. Sweet cherry exhibited antibacterial action against MDR organisms S. aureus, K. pneumoniae, and P. aeruginosa owing to its amphipathic characteristics (211).

The complete plant ethanol extract of Maidenhair fern and Chirayita is effective against S. aureus, and E. faecium. The extract of maidenhair fern possesses astringent, demulcent, expectorant, and diuretic characteristics, successfully addressing urinary tract infections (212). Chirayita extract is utilized for inflammation, hepatitis, digestive disorders, chronic fever, malaria, dermatological conditions, and bronchial infections. Both extracts combat infections via amphipathicity (212). The extract from aerial portions addresses pruritus, viral inflammatory dermatoses, malaria, and typhoid, specifically targeting E. faecium and P. aeruginosa through electrostatic interactions. Timber fruit extract addresses cancer, gastrointestinal disorders such as cholera and dysentery, and oral infections including toothaches and mouth ulcers. It additionally targets E. faecium and S. aureus through electrostatic interactions (212).

Shobha et al. (213) investigated the antibacterial properties of an ethanol extract derived from cashew leaves. The herb is conventionally utilized for venereal disorders, gastrointestinal issues, dermatological conditions, stomatitis, bronchitis, psoriasis, dental pain, and periodontal infections. The extract comprises hydrophobic and hydrophilic residues, hence demonstrating MDR antibacterial action against S. aureus, K. pneumoniae, and P. aeruginosa (213).

Chandrasekharan et al. (214) investigated the therapeutic applications and mechanisms of several medicinal plant extracts against MDR microorganisms. The pipli root aqueous extract and the ethanol extract of Bermuda grass leaves function via electrostatic interactions. Pipli root extract is recognized for its antioxidant and anti-inflammatory activities, especially against E. faecium and A. baumannii (214). The ethanol extract of Bermuda grass leaves serves as a laxative, tonic for the brain and heart, and a cooling agent to eliminate S. aureus (214). The hexane extract of lemongrass modulates hypertension, epilepsy, and gastrointestinal and central nervous system problems, specifically targeting P. aeruginosa and E. faecium via ionic interactions (214). Aloe extract facilitates wound healing, mitigates inflammation, and addresses burn-related skin injuries by rebuilding compromised skin. It targets P. aeruginosa and Enterococcus casseliflavus through amphipathicity, encompassing hydrophobic and hydrophilic residues (214).

Nayim et al. (215) indicate that certain plant extracts exhibit significant antibacterial efficacy against MDR bacteria due to ionic interactions. Methanol extracts from cocoa seeds, bush butter tree, and okra leaves suppress MDR K. pneumoniae, but sweet potato leaf extract targets the same bacteria through amphipathicity (215). These plants possess traditional therapeutic applications: cocoa seeds for disorders such as dermal injuries and diarrhea, bush butter tree for tonsillitis, okra leaves for infections, and sweet potato leaves for conditions including diabetes and inflammation (215).

Likewise, extracts from neem tree bark and pomelo leaves demonstrate efficacy against MDR Enterobacter species via electrostatic interactions (215). Neem bark is typically utilized for dermatological conditions and febrile illnesses, whereas pomelo leaves are employed for neurological problems and hemorrhagic conditions (215). Winter squash bean extract, utilized in traditional therapy for renal and gastrointestinal ailments, also addresses MDR Enterobacter and K. pneumoniae via amphipathicity (215). Ultimately, common bean leaf extract suppresses MDR E. casseliflavus and is commonly utilized for diabetes and weight management (215).

Subramani et al. (216) identified multiple plants demonstrating MDR activities. The methanol extract of Lantana leaves yields secondary compounds that mitigate inflammation, combat malaria, alleviate spasms, suppress tumor proliferation, avert ulcer development, and specifically target Enterobacter species and P. aeruginosa through electrostatic interactions (216). The alcoholic extract of myrtle leaves showed efficacy against S. aureus and P. aeruginosa via electrostatic interactions (216). It addresses cancer, inflammation, diabetes, ulcers, hypertension, diarrhea, and rheumatism. Extracts of Palash (Butea monosperma) leaves (ethanol, hexane, and water) enhanced diuresis and menstrual flow while suppressing Enterobacter species through ionic interactions (216). The ethanol extract of Burflower (Neolamarckia cadamba) tree leaves and bark alleviated fever, uterine ailments, skin problems, and inflammation, while also functioning as a febrifuge, antidiarrheal, antihyperglycemic, and antibacterial agent against A. baumannii and P. aeruginosa, attributed to their amphipathic characteristics (216).

Masoumian and Zandi (217) demonstrated the therapeutic efficacy of various plant extracts against MDR species. The extract of cinnamon bark water is efficacious in managing diabetes, reducing oxidative stress, and mitigating inflammation. This extract shows efficacy against S. aureus and P. aeruginosa due to ionic interactions (217). Similarly, medicinal Aloe leaf water extracts precisely target S. aureus and P. aeruginosa, facilitating the treatment of digestive issues and burns via ionic interactions. The aqueous extract of mint leaves has shown efficacy against acid reflux, irritable bowel syndrome, and the common cold (217). It demonstrated efficacy against S. aureus and P. aeruginosa owing to its amphipathic metabolites, enabling the extract to engage concurrently with hydrophobic and hydrophilic residues (217). The aqueous extract of henna leaves exhibited antibacterial activity against S. aureus and P. aeruginosa via electrostatic interactions. It proficiently addressed burns, wounds, and cutaneous infections while enhancing hair vitality (217).

Likewise, the chloroform extract of snake flower leaves effectively addressed skin and wound infections due to the hydrophobic properties of the plant extract (218). Ghuman et al. (219) showed that chloroform extract from bitter Aloe leaves can address skin problems by targeting S. aureus, P. aeruginosa, and A. baumannii. The extract’s efficacy stemmed from its capacity to adhere to the hydrophobic groups located in the bacterial membrane (219). Furthermore, the ethanol extract of hrse mint (Mentha longifolia) aerial parts significantly mitigated throat and oral discomfort, addressing sore throats and targeting Mycobacterium tuberculosis through its amphipathic characteristics (219).

Agarwal et al. (220) indicated that the ethanol extract of Phyllanthus emblica (Indian gooseberry) aerial parts could effectively target M. tuberculosis and MRSA via electrostatic interactions (220). Moreover, the dichloromethane extract of tree Aloe leaves demonstrated effectiveness in addressing skin, gastrointestinal, and respiratory ailments, countering S. aureus and P. aeruginosa owing to their hydrophobic properties (220). Bacha et al. (221) examined the antibacterial efficacy of methanol extract from cardamom (Elettaria cardamomum ) fruit against S. aureus. The mechanism of action entails ionic and electrostatic interactions that result in the deposition of the plant extract on the bacterial cell membrane, inducing instability and disintegration of the cellular membrane (221).

Additionally, Arullappan et al. (222) demonstrated that the leaf extract of Clinacanthus nutans had a notable antifungal activity against C. albicans in a laboratory environment, with MIC above 1 mg/ml. Numerous research, including those by Ortega‐Ramirez et al. (223), Ma et al. (224), and Shanmugam et al. (225), have elucidated the antibacterial characteristics of Allium cepa (onion). Zhou et al. (226) demonstrated that a gel including Durio zibethinus polysaccharide at a dose of 100 mg/mL efficiently suppresses the proliferation of oral infections. Diris et al. (227), and Apridamayanti et al. (228) reported the antibacterial properties of Malabar melastome (Melastoma malabathricum). The inhibitory activity of this plant extract may be ascribed to its phenolic constituents, such as flavonols and ellagic acid (229).

Under laboratory conditions, the fruit extract of Cucurbita maxima (Buttercup squash) has demonstrated antibacterial efficacy against S. aureus, Bacillus subtilis, and Micrococcus luteus (230). The constituent of this fruit, which comprises caffeic acid and p-coumaric acid, possesses antibacterial properties (230). Numerous research studies have demonstrated the antibacterial efficacy of Zingiber cassumunar (cassumunar ginger) essential oil against dermatophytes (231, 232). Research conducted by (33) demonstrated that the traditional herbal preparation known as “Loloh,” commonly prepared as a decoction on Bali Island, is effective in treating several ailments caused by pathogens, including diarrhea and dysentery. Numerous investigations have demonstrated the antibacterial efficacy of Andrographis paniculata (green chiretta) under in vitro conditions against Gram-positive and Gram-negative bacteria (233–235).

Andrographolide, the principal active constituent from the stem and leaves of Andrographis paniculata, has demonstrated significant efficacy as an anti-diarrheal agent in clinical trials and is accountable for the plant’s antibacterial properties (236, 237). The antibacterial properties of Blumea balsamifera (ngai camphor), Jatropha curcas (barbados nut), and Lablab purpureus (hyacinth bean) have been recorded in the literature reviewed by Priya and Karthika (238) and Rampadarath et al. (239).

Women in Minahasa, North Sulawesi, Indonesia, frequently utilize Baker, a traditional herbal steam bath, for thermotherapy, aromatherapy, and postpartum recuperation. Alexa et al. (240) indicated that 31 species utilized in “Baker” produce essential oils, including Citrus hystrix, Curcuma xanthorrhiza, Cymbopogon citratus, Cymbopogon nardus, Myristica fragrans, and Syzygium aromaticum. The volatile oil constituents (eugenol, β-pinene, sabinene, and zingiberene) linked to the medicinal benefits of these plants have been identified (240).

Eugenol derived from Syzygium aromaticum (clove) exhibited antibacterial properties against S. aureus ATCC 29213 and MRSA clinical isolates. Furthermore, it impeded the production of biofilms, hence diminishing the colonization of S. aureus in vivo (241). It efficiently eradicates existing biofilms, diminishes the expression of genes linked to biofilms and enterotoxins, disrupts the cell membrane, and results in the release of cellular contents (241). Moreover, eugenol has demonstrated antifungal capabilities and the capacity to inhibit oral microorganisms associated with periodontal disease and dental caries (242–244). Eugenol is readily accessible and utilized as a counterirritant, topical antiseptic, and in dentistry, frequently coupled with zinc oxide for analgesia and root canal obturation (244, 245).

Numerous bioactive chemicals in medicinal plants, including terpenoids, flavonoids, and alkaloids, engage with microbial cell membranes, resulting in structural impairment. These chemicals can enhance membrane permeability, resulting in the efflux of cellular constituents and subsequent cell death (173, 182, 208). Compounds such as carvacrol (derived from oregano) and thymol (extracted from thyme) compromise the lipid bilayer of bacterial membranes, undermining their structural integrity (173, 208).

Moghrovyan and Sahakyan (246) revealed that essential oils derived from Origanum vulgare compromised the membrane potential of E. coli and S. aureus, resulting in cell lysis (246). Alkaloids derived from Dicranostigma leptopodum enhance the permeability of K. pneumoniae cells, impeding their development (246). Due to their lipophilic characteristics, terpenes easily infiltrate bacterial cell membranes, resulting in damage and demonstrating antibacterial or bactericidal properties, as evidenced by carvacrol, thymol, and eugenol against several bacterial strains (247). Flavonoids similarly compromise the cell membranes of Candida species, increasing permeability and disrupting membrane protein functionality (247). Furthermore, the alkaloid tomatidine, present in potatoes, inhibits the enzymes involved in ergosterol production in many species of Candida and Saccharomyces (248).

Flavonoids exhibit potential as antimicrobials by blocking bacterial fatty acid biosynthesis enzymes, such as quercetin, apigenin, and sakuranetin from Plukenetia volubilis leaves, which target specific enzymes in H. pylori (249). These flavonoids, such as quercetin and apigenin, inhibit peptidoglycan production, an essential component of the bacterial cell wall (249). In fungi, acidic terpenoids such as enfumafungin block β (1, 3)-D-glucan synthase, an enzyme essential for glucan production in the cell wall, by a non-competitive mechanism (250). Furthermore, the flavonoid glabridin compromises the structural integrity of fungal cell walls, illustrating an alternative mechanism for antifungal action (251).

Plant-derived chemicals provide many techniques to address microbial resistance, especially via inhibiting efflux pumps (252). Efflux pumps constitute a primary mechanism of antibiotic resistance in MDR bacteria. Medicinal herbs possess chemicals that can obstruct these pumps, so limiting the evacuation of antibiotics and augmenting their effectiveness (252). The many methods, such as membrane rupture, interference with biosynthesis and metabolism, biofilm inhibition, and reactive oxygen species formation, underscore the potential of plant-derived chemicals, particularly those from the Caucasus region, to address antimicrobial resistance (252). Flavonoids and alkaloids, including berberine (derived from Berberis species), interact with efflux pump proteins, inhibiting their activity (182, 208, 252).

Yu et al. (252) emphasized that berberine blocked the NorA efflux pump in MRSA, hence reversing resistance to ciprofloxacin. Alkaloids, including ellagic and tannic acids, together with different flavonoids, impede efflux pump activity in bacteria such as A. baumannii (253). Terpenes, notably carvacrol, serve as effective inhibitors of efflux pumps, particularly in S. aureus, possibly via influencing gene expression or binding to efflux proteins (254). Curcumin, a polyphenol, regulates efflux pump activity in yeast, whereas many flavonoids exhibit comparable inhibitory effects in fungi, resulting in cellular mortality (254).

Biofilms are protective matrices created by MDR microorganisms, rendering them resistant to antibiotics. Compounds derived from medicinal plants can impede biofilm growth or dismantle pre-existing biofilms (255). Polyphenols and tannins disrupt quorum sensing, a critical communication mechanism for biofilm development (255). Flavonoids and alkaloids exhibited notable antibiofilm efficacy against several microbial species. Flavonoids, including phloretin, can impede biofilm development in E. coli by downregulating curli gene expression, hence limiting fimbriae formation (255). They can also elicit aberrant multicellular aggregation in S. aureus, inhibiting the formation of structured biofilm formations (155). Alkaloids such as anguinarine and berberine derived from apple significantly inhibit biofilm formation in Proteus rettgeri and MDR E. coli, respectively, by disrupting the synthesis of biofilm-related compounds (256).

Moreover, some flavonoids (quercetin, apigenin) and phenolic acids (ellagic, caffeic) impede biofilm formation in Candida species, including the drug-resistant Candida auris (257). Prenyflavanone 8PP inhibits C. albicans biofilms by enhancing the generation of reactive oxygen and nitrogen species (257). Curcumin from Curcuma longa suppresses biofilm formation in P. aeruginosa via downregulating quorum sensing-related genes (258).

Compounds from medicinal plants can inhibit essential enzymes critical for microbial survival, including DNA gyrase, topoisomerase, and β-lactamase. Alkaloids and phenolic acids attach to the active sites of these enzymes, hindering DNA replication and cellular division (259). Bioactive phytochemicals interfere with bacterial metabolism via multiple methods. Bioflavonoids can impede the F1 or membrane-associated F1Fo ATPases of E. coli (259). Catechin and epigallocatechin gallate inhibit F1Fo-ATPase and lactate dehydrogenase in Streptococcus mutans (259). Flavonoids derived from Chimonanthus salicifolius SY also influence ATPase activity in P. aeruginosa and S. aureus, impeding their development (259).

Berberine derived from Corydalis turtschaninovii modifies glucose metabolism in Streptococcus pyogenes via regulating carbohydrate absorption and transformation (260). Moreover, terpenes have antifungal properties against several fungi by obstructing respiratory enzymes such as succinate dehydrogenase and NADH oxidase. Moreover, epigallocatechin gallate (EGCG) derived from green tea decreased β-lactamase activity in K. pneumoniae, hence reinstating susceptibility to β-lactam drugs (261).

Numerous plant-derived chemicals, including quinones and polyphenols, produce reactive oxygen species in microbial cells, surpassing their antioxidant defenses and inducing oxidative damage (262). Reactive oxygen species inflict damage on DNA, proteins, and lipids, resulting in cellular apoptosis (262). The antibacterial efficacy of catechin against Gram-positive and Gram-negative bacteria is ascribed to the induction of reactive oxygen species subsequent to membrane permeabilization. Likewise, berberine induces elevated reactive oxygen species generation in S. pyogenes (262).

In Candida species, the flavonoid baicalein induces reactive oxygen species buildup and consequent death. Moreover, honey flavonoids and quercetin impede the growth of C. albicans by increasing intracellular reactive oxygen species levels (263). Santra et al. (264) demonstrated that plumbagin, derived from Plumbago zeylanica, produced oxidative stress in C. albicans, leading to fungal cell death (264).

Certain medicinal plants augment the host immune system, enhancing its capacity to combat MDR microorganisms. Polysaccharides and saponins activate immune cells, including macrophages and neutrophils, to phagocytize infections (265). Natural immunostimulants, such as probiotics and traditional Chinese medicines, are progressively utilized as animal feed additives to manage Salmonella pullorum infections, owing to their environmentally favorable characteristics and absence of chemical residues (265). Zanthoxylum bungeanum meal, a byproduct of oil production, possesses bioactive chemicals and exhibits extensive antibacterial activity (265).

Likewise, Schisandra chinensis and Scutellaria baicalensis exhibit anti-inflammatory, antioxidant, and antibacterial characteristics and are recognized for their ability to improve animal development and productivity (265, 266). Conversely, Abdelmotaleb et al. (267) reported that Echinacea purpurea extracts augmented macrophage function against MDR M. tuberculosis.

Herbal medicines frequently demonstrate synergistic effects when used in conjunction with antibiotics, hence augmenting their effectiveness against MDR pathogens (208, 268). Phytochemicals can diminish microbial defenses, rendering them more vulnerable to drugs. Hasna et al. (268) examined the synergistic effects of methanolic extracts from four Algerian medicinal plants (garlic, red onion, cumin, and fenugreek) in conjunction with several strains of lactic acid bacteria against H. pylori. The in vivo antibacterial efficacy of fenugreek extract in conjunction with Bifidobacterium breve was assessed to validate the synergistic impact of this particular combination on H. pylori colonization (268). All evaluated combinations of plant extracts and probiotics exhibited inhibitory activity against H. pylori, but with differing degrees of efficacy (268).

Saquib et al. (269) examined the synergistic antibacterial properties of ethanolic extracts from Punica granatum (pericarp), Commiphora molmol, and Azadirachta indica (bark) in conjunction with standard antibiotics (amoxicillin, metronidazole, tetracycline, and azithromycin) against principal periodontopathic bacteria (Porphyromonas gingivalis, Tannerella forsythia, Treponema denticola, and Aggregatibacter actinomycetemcomitans). Synergistic antibacterial action was noted when plant extracts were coupled with antibiotics, with the most effective synergy observed between P. granatum extract and amoxicillin against A. actinomycetemcomitans (269). Magryś et al. (270) observed that the combination of Allium sativum (garlic) extract with amoxicillin considerably decreased the MIC against MDR H. pylori.

Ayaz et al. (271) conducted a study to investigate the antibacterial efficacy and minimum bactericidal concentration (MBC) of three particular agents (thymol, EDTA, and vancomycin) against both susceptible and resistant bacterial strains. The research also examined the synergistic effects of thymol and EDTA, as well as the interactions of vancomycin with these two compounds (271). Thymol exhibited significant bactericidal activity, with MBC between 60 and 4000 g ml/1. Conversely, EDTA exhibited bacteriostatic activity solely beyond the MBC range of 60-4000 g ml/1 (271).

Gram-positive bacteria demonstrated MICs between 0.125 and 16 g ml/, whereas Gram-negative bacteria displayed MICs from 32 to 128 g ml/1. The interaction mechanism between various chemical combinations and MRSA and E. coli was examined by checkerboard dilution and time-kill curve assays (271).

Medicinal plants can inhibit the synthesis of virulence components, including toxins and adhesion molecules, hence diminishing the pathogenicity of MDR microorganisms (208, 272). Compounds such as resveratrol and quercetin inhibit the expression of genes that encode virulence factors. Resveratrol, derived from grapes, suppressed the synthesis of staphylococcal enterotoxins in MRSA (272). El-Mahdy et al. (273) suggested that resveratrol and curcumin may serve as alternative treatment strategies for treating MRSA infections by diminishing toxin production.

In contrast to single-molecule antibiotics, medicinal plants comprise a complex array of bioactive chemicals, such as alkaloids, terpenoids, flavonoids, phenolics, and others. The “cocktail” effect poses a distinct challenge to bacteria striving to acquire resistance (320). Unlike conventional medicines that typically target a singular bacterial route, plant extracts frequently demonstrate antimicrobial activity via many pathways (320). This complex assault substantially complicates the ability of microorganisms to evolve resistance, as they are required to create several resistance mechanisms simultaneously (320). Several factors influence the development of resistance (320), as outlined below:-

Medicinal plants contain a substantial array of bioactive chemicals with various modes of action. These chemicals may potentially surmount the resistance mechanisms established by MDR bacteria. The intricate amalgamation of phytochemicals in medicinal plants can demonstrate synergistic effects, wherein the collective activity surpasses the sum of its individual constituents. This combination can augment antibacterial efficacy and diminish the probability of resistance emergence.

Maintaining uniform quality and effectiveness of plant-derived pharmaceuticals is essential. This necessitates uniform growing procedures, extraction techniques, and quality control protocols to ensure the consistency of active chemicals. Comprehensive scientific research is essential to confirm the effectiveness and safety of therapeutic plants against MDR bacteria. This includes in vitro and in vivo investigations to ascertain the mechanisms of action, ideal doses, and possible toxicity. Furthermore, the overexploitation of therapeutic plants may result in their depletion. Sustainable harvesting methods and conservation initiatives are crucial for guaranteeing the enduring availability of these precious resources.

Medicinal plants can provide innovative lead chemicals for the development of new antibiotics. Advanced methodologies like genomics, proteomics, and metabolomics help expedite the identification and characterization of bioactive compounds. Integrating plant-derived antimicrobials with current antibiotics can augment their efficacy and address resistance. This method can help decrease the dosage of traditional antibiotics, hence reducing adverse effects and the emergence of further resistance. Comprehending the interplay between phytochemicals and specific patients can facilitate tailored therapeutic approaches. This method considers personal genetic composition, gut microbiota, and additional variables to enhance the efficacy of phytotherapeutics.

Combining traditional knowledge of medicinal plant usage with contemporary scientific studies can yield significant insights into their effectiveness and safety. Collaboration among scientists, healthcare practitioners, and traditional healers is crucial for converting research findings into applicable clinical practices. Moreover, exchanging information and resources among nations helps expedite the discovery and development of novel plant-based pharmaceuticals to address MDR bacteria globally. By confronting the problems and seizing the opportunities, medicinal plants can significantly contribute to combating MDR bacteria, providing a sustainable and potentially transformative healthcare solution.