Candidates for antibacterial drugs include cytotoxic and anticancer drugs. However, due to their cytotoxicity or genotoxicity profile, they can be considered as having high clinical value, mainly in the treatment of infections in oncological patients (Gouveia et al., 2023).

One of the concerned anticancer substances is floxuridine, a derivative of 5-fluorouracil, which has demonstrated antibacterial activity against S. aureus strains, including methicillin resistance S. aureus (MRSA), and S. epidermidis. It is important in research on this drug to optimize the structure of the drug molecule so that it is not activated in human cells and does not have a cytotoxic effect on them (Thangamani et al., 2015; Younis et al., 2017; Cheng et al., 2019; Hua et al., 2022). Ethyl bromopyruvate, a derivative of 3-bromopyruvic acid, demonstrated antibacterial activity against strains of the ESKAPE group. The authors of the study proved that 24-h bromopyruvate therapy can achieve the same effects as vancomycin therapy. Additionally, this compound was responsible for inhibition of iron uptake, by Mycobacterium tuberculosis (Kumar et al., 2019a).

It has also been proven that oncological drugs can be effective in combination therapy with antibiotics. Mitoxantrone, in combination with colistin was effective in the treatment of P. aeruginosa infections and biofilm control (Torres et al., 2018). In turn, mitotane with polymyxin B resulted in an increased antibacterial activity against isolates resistant to this antibiotic and carbapenem-resistant A. baumannii, P. aeruginosa, and K. pneumoniae. In this combination, polymyxin B, due to its action on the outer membrane of Gram-negative bacterial cells, allowed the oncological drug to penetrate into them (Tran et al., 2018).

Research on the repositioning of this group of drugs in infectious diseases is currently under investigation in the preclinical phase. At present, clinical trials on the repositioning of anticancer drugs mainly concern the treatment of Alzheimer’s disease. They are believed to have the ability to regulate processing and reduce the aggregation of amyloid plaques (Advani and Kumar, 2021). It has been shown that the use of these drugs in oncological diseases reduced the risk of developing dementia (Ancidoni et al., 2021).

The development of tyrosine kinase inhibitors (TKIs) represents one of the most significant milestones in the medicine of the 21st century. The first TKI, imatinib, was designed to target the BCR-Abl hybrid protein, produced in patients with Philadelphia-chromosome-positive chronic myelogenous leukemia. Since the introduction of imatinib, the application of TKIs has been ever-expanding, but has addressed mainly oncological patients (Thomson et al., 2023). Several signaling pathways have gained attention as potential targets for repurposing of TKIs for other diseases; these include pulmonary arterial hypertension (PAH), as a platelet-derived growth factor receptor, or mast/stem cell growth factor receptor kit (c-KIT), can contribute to inflammation and proliferation processes being involved in the pathogenesis of the disease. The results from experimental studies with imatinib were promising, and oral application yielded improvements in exercise capacity and hemodynamics in clinical trials; however its further development was limited by systemic side effects with subdural hematomas (Weatherald et al., 2020). Currently, research is underway on the repositioning of TKIs in the treatment of Human Immunodeficiency Virus (HIV) infection. In vitro studies have shown that TKIs have the ability to modulate the immune response and have antiviral activity against not only HIV-1 virus but also Cytomegalovirus (CMV), Monkeypox virus (MPV), Varicella zoster virus (VZV), and filoviruses. The greatest hopes are associated with the repositioning of TKIs in viral diseases due to the inhibition of the escape of viruses from infected cells, thus reducing the spread of infection (Ananthula et al., 2018; Climent and Plana, 2019; Vigón et al., 2020; Rodríguez-Agustín et al., 2023).

Research on the antibacterial activity of TKIs is currently in the preclinical phase; however, studies have identified two candidates. Fostamatinib was considered a molecule with anti-tuberculosis activity. It inhibits the activity of protein kinases (serine/threonine-protein kinase) found in M. tuberculosis and M. bovis. This drug was found to kill infected macrophages and did not show cytotoxicity (Rodrigues et al., 2020). Ponatinib also demonstrated antibacterial activity against planktonic cells and biofilm-forming Streptococcus mutans (Saputo et al., 2018).

Selective estrogen receptor modulators (SERMs) are used in the treatment of cancer and in the prevention of osteoporosis in postmenopausal women. Examples of SERMs are tamoxifen, toremifene, raloxifene, and clomiphene. In addition to its listed indications, tamoxifen is also used to treat infertility and reduce the risk of breast cancer in women. These drugs compete with estrogen and prevent its binding to the estrogen receptor, thus inhibiting its stimulating effect. They also induce apoptosis and regulate the expression of oncogenes and growth factors. Moreover, they also demonstrate various pleiotropic neuroprotective, cardioprotective, and antimicrobial effects (Garg et al., 2020).

The SERM clomiphene demonstrated antibacterial activity against strains of Bacillus subtilis, E. faecium and methicillin-resistant staphylococci. It is believed to act by influencing a bacterial cytoplasmic enzyme important for the synthesis of teichoic acid. Its inhibition leads to impaired cell wall synthesis of Gram-positive bacteria. In the case of Gram-negative bacteria, clomiphene have been found to have an effect in combination with colistin. In these bacteria, this SERM member appears to influence the synthesis and transport of lipopolysaccharide precursors (Younis et al., 2017; Torres et al., 2018).

Toremifene has also demonstrated antibacterial activity. When applied in combination with polymyxin B, it is characterized by a strong antibacterial effect against P. aeruginosa bacterial cells, which form biofilms and are usually resistant to these antibiotics. Toremifene induced depolarization of the cytoplasmic membrane, increased permeabilizing activity and stimulated the production of reactive oxygen species in bacterial cells. It is believed that by influencing the permeability of bacterial cell membranes and lipopolysaccharides, polymyxins enable SERMs to better penetrate microbial cells. Unlike the previously-mentioned SERMs, tamoxifen interacts with lipids in bacterial membranes, causing structural changes that may result in cell lysis. Its analogues, however, induce the outflow of ions from Gram-negative bacterial cells and lead to the loss of their membrane potential (Hussein et al., 2017). In addition, SERM drugs have also shown activity against viruses, fungi, and parasites (Johansen et al., 2013; Garg et al., 2020). One clinical study assessed the safety and effectiveness of tamoxifen in combination with amphotericin B and fluconazole in the treatment of cryptococcal meningitis (NCT03112031), but failed to obtain satisfactory results.

Potential mechanisms of action of the drugs listed in this section are presented in Figure 2 (Johansen et al., 2013; Younis et al., 2017; Saputo et al., 2018; Torres et al., 2018; Tran et al., 2018; Garg et al., 2020; Advani and Kumar, 2021; Li et al., 2023).

Non-steroidal anti-inflammatory drugs (NSAIDs) are one of the most frequently-prescribed therapeutic groups, with the “basic” mode of action covering the inhibition of COX enzymes and reduction of release of prostaglandins (PGs) and thromboxane (TxA). While inhibition of COX isoforms has been demonstrated as a primary mechanism for the efficacy of the NSAIDs, preclinical and clinical data have revealed the presence of additional COX-independent mechanisms. These include the inhibition of various transcription factors: activator protein 1 (AP-1) and nuclear factor-kappa B (NF-ĸB) regulating the expression of various pro-inflammatory cytokines (TNFα, IL-1β, IL6) and mediators (NO, PGE2, ICAM-1, VCAM-1) inhibiting signaling pathways involved in inflammatory processes (MAPK and PI3K/AKT) modulating nuclear receptors (PPAR-γ and PPAR-δ) inhibiting leukocyte and neutrophil adherence, inhibiting matrix metalloproteinases (MMP2 and MMP9) or inhibiting cAMP-specific phosphodiesterase (PDE) IV. Some of these mechanisms may support the rationale for in vitro/in vivo studies on the antiproliferative, antimetastatic, antiangiogenesis, and neuroprotective effects of NSAIDs. Due to these multifactorial effects, they may represent promising candidates for repurposing for chemoprevention and cancer treatment (Ozleyen et al., 2023).

Antibacterial activity has been demonstrated, among others, by acetylsalicylic acid, diclofenac, ibuprofen, celecoxib and fenamic acids. While indomethacin, meloxicam, naproxen, nimesulid, and paracetamol have also demonstrated antibacterial activity, the possibility of using them in the treatment of infections requires further research (Foletto et al., 2021a). Acetylsalicylic acid (ASA) inhibited the production of alpha toxin and negatively influenced the expression of genes responsible for adhesion to components of the host extracellular matrix in S. aureus strains, including methicillin-resistant ones (Barbarossa et al., 2022). ASA has been found to have a synergistic effect with vancomycin in an animal model of endocarditis (Brown, 2015). Currently, studies are underway to use the indicated anti-inflammatory drug to reduce mortality in HIV-infected tuberculosis patients (NCT04145258, phase 3 clinical trial, currently recruiting) (Maitre et al., 2022). Another example of an NSAID drug that has demonstrated antimicrobial activity is ibuprofen. It inhibited the growth of E. coli and P. aeruginosa, as well as S. aureus strains under low pH conditions. Additionally, ibuprofen also reduced the rate of bacterial cell accumulation during biofilm formation by P. aeruginosa cells (Barbarossa et al., 2022). An ongoing clinical trial, currently in the recruitment phase, is focusing on the use of acetylsalicylic acid and ibuprofen as adjunctive therapy in the treatment of both sensitive and multidrug-resistant tuberculosis (NCT04575519).

Diclofenac is another molecule of interest for studies on drug repurposing due to its properties to inhibit biofilm formation on the dentin after topical usage (Barbarossa et al., 2022). Studies have also shown that it might inhibit the number of viable E. coli and Mycobacterium cells when given in combination with streptomycin, and to have an antibacterial effect against Listeria spp. strains when given with gentamycin (Brown, 2015; Foletto et al., 2021a). In vitro studies also found combined diclofenac and oxacillin to be effective against MRSA strains. The use of these two substances led to apoptosis of bacterial cells through damage to the cell membrane and breaks in the DNA (Queiroz et al., 2021). Diclofenac also inhibited the multiplication of MDR clinical isolates of E. coli, A. baumannii, S. aureus, and S. epidermidis (Foletto et al., 2021a); however, its antibacterial effects were only observed at very high doses (Brown, 2015). Research is currently underway on its new derivatives with better properties (Hamed et al., 2023; Tolba et al., 2023). So far, the use of diclofenac has also been considered in the treatment of various types of cancer (Pantziarka et al., 2016).

Celecoxib has demonstrated antibacterial activity against both Gram-negative and Gram-positive bacterial strains. It improved the sensitivity of M. smegmatis and MRSA strains to antimicrobial therapy by increasing the uptake of antibiotics by bacterial cells; this was observed when the drug was used either locally or systemically. Depending on the dose used, celecoxib could also inhibit RNA, DNA and proteins synthesis and reduce the level of pro-inflammatory cytokines (Bak and Krupa, 2023). Interestingly, it has also been shown to be effective against Francisella tularensis strains causing tularemia (Chiu et al., 2009). Research conducted to determine effective and safe doses of celecoxib in antibacterial therapy identified structural analogues with strong antimicrobial activity. These molecules were able to improve the effectiveness of polymyxins against multidrug-resistant Gram-negative bacteria and were active against MRSA strains (Krishnamurthy et al., 2019). Current clinical trials are focused on evaluating the activity of celecoxib in the treatment of tuberculosis (NCT02602509, completed, no study results) and in viral suppression in chronic hepatitis B (NCT05256823, pre-recruitment). In addition to its antimicrobial activity, celecoxib has also shown good results as a possible drug in anticancer therapy (Bak and Krupa, 2023).

Fenamic acid derivatives, tolfenamic acid, flufenamic acid, and mefenamic were effective against Neisseria gonorrhoeae strains. Importantly, these compounds did not affect commensal Lactobacillus spp. Fenamic acid derivatives showed better properties in reducing the intracellular load of N. gonorrhoeae in infected cells compared to ceftriaxone and reduced the expression of pro-inflammatory cytokines in cervical cells (Seong et al., 2020).

The use of nonsteroidal anti-inflammatory drugs in the treatment of infections has great potential due to the possibility of use in both local and systemic therapy. However, preclinical and clinical phase studies will also have to determine a safe dose. Combination therapy with NSAIDs and antibiotics has demonstrated synergy and seems to be a good solution.

The drugs used in general and local anesthesia inhibit the activity of the nervous system by suppressing synaptic transmission; this is believed to result from the intensification of inhibitory processes, or suppression of stimulatory processes associated with such activity. Administration thus causes reversible loss of consciousness, amnesia, immobility and analgesia (Tesoro et al., 2020; Hogarth et al., 2023). Due to the interaction with γ-aminobutyric acid (GABA), N-methyl-D-aspartate (NMDA), glycine, glutamic acid, nicotinic acetylcholine receptors and, equally importantly, with voltage-dependent sodium, potassium, and calcium channels, it blocks the depolarization of the nerve cell membrane (Yang et al., 2024). In addition to their anesthetic effect, some drugs from this group, such as ketamine, propofol or lidocaine, have demonstrated in vitro anticancer activity by preventing cell proliferation and inducing apoptosis (Zhou et al., 2020; Wu et al., 2022). Research is also underway on the possibility of their use in the treatment of anorexia nervosa (NCT04714541) or postpartum depression (NCT03927378, NCT05907213).

Some anesthetic drugs also have antimicrobial activity. In vitro, studies have confirmed the effectiveness of ketamine against strains of P. aeruginosa, E. faecalis, S. pyogenes, S. epidermidis and S. aureus, including those resistant to methicillin (Begec et al., 2013; Coutinho et al., 2021; Sokolowska et al., 2023). The drug is believed to induce apoptosis by altering the integrity of the cell membrane and damaging bacterial DNA. It has also demonstrated affinity for sortase A, which is an important virulence factor in staphylococci. This enzyme is responsible for the acquisition of iron from host cells, the adhesion of bacteria to the extracellular matrix of the host, and the evasion of its immune system. A similar mechanism of antibacterial activity occurs in the case of lidocaine and procaine, these damage the bacterial cell membrane, leading to changes in permeability and ion outflow within the bacterial cell (Coutinho et al., 2021). An ongoing clinical trial (NCT04843982, in the recruitment phase) aims to evaluate the anti-inflammatory effect of one of the ketamine stereoisomers in the acute phase of sepsis. Research on the possibility of repositioning anesthetic drugs in the treatment of infectious diseases is currently in the preclinical phase.

The potential mechanisms of antimicrobial action of drugs used in pain therapy are presented in Figure 4 (Chiu et al., 2009; Begec et al., 2013; Maitre et al., 2022; Ferrer-Luque et al., 2023; Tabatabaeifar et al., 2023).

The first generation of typical antipsychotic drugs, e.g., including haloperidol, fluphenazine, thioridazine and loxapine, were first used in the 1950s. The act by regulating the neurotransmitters in the brain, most important by blockading the D2 dopamine receptor (Weston-Green, 2022). Atypical antipsychotics, such as olanzapine or quetiapine, are characterized by high affinity for 5-HT2 receptors. Drugs in this group are considered capable of binding to multiple therapeutic targets, resulting in multiple mechanisms of action. They interact not only with neurotransmitter receptors, but also have the ability to suppress NF-kB, deregulate cyclins, or phosphorylate β-catenin (Awuah et al., 2023).

Antipsychotics are used to treat mental disorders and psychoses, especially schizophrenia and bipolar disorder (Vitiello et al., 2009; Lin et al., 2022). Research indicates the possibility of their use as complementary drugs in anticancer therapy, and this has been the subject of several clinical trials (Vlachos et al., 2021). The anticancer effect may result from modulation of various signaling pathways as well as autophagy, and influencing changes in cell membrane permeability and cell metabolism (Rácz and Spengler, 2023). For example, chlorpromazine and thioridazine have been included in clinical trials as an adjunct in cancer treatment, as well as in the treatment of migraine (NCT05190315, NCT05967442) (Aslostovar et al., 2018; Cohen and Friedman, 2021).

Among the antipsychotics, flupentixol, thioridazine, and prochlorperazine have demonstrated antibacterial activity. They may act by inhibiting the enzymes influencing the bacterial cell membrane and antibiotic efflux pumps (Barbarossa et al., 2022; Hua et al., 2022). It has been demonstrated that phenothiazines can reduce the ability of microorganisms to adhere to endothelial cells and can interfere with the action of ATPases, which inhibits bacterial replication (Barbarossa et al., 2022). Prochlorperazine was found to have antibacterial activity against Gram-negative and Gram-positive bacteria by infuencing the functioning of efflux pumps. Flupentixol, in turn, reduced the membrane potential in S. aureus cells (Hua et al., 2022). Importantly, a study on urinary catheters found chlorpromazine to be effective against the bacterial species most commonly implicated in urinary tract infections, i.e., E. coli, P. mirabilis and Klebsiella spp.; hence it may be suitable for coating urological instruments and preventing urinary tract infections (Sidrim et al., 2019).

Interestingly, thioridazine, withdrawn from treatment of schizophrenia due to cardiotoxicity, turned out to be effective against methicillin-sensitive and methicillin-resistant strains of S. aureus, Enterococcus spp., and M. tuberculosis, M. avium (Kristiansen et al., 2007; Deshpande et al., 2016; Ruth et al., 2020). Also, among the phenothiazine derivates, it also the most promising candidate for use as an antituberculosis drug; it inhibits the action of efflux pumps and increases the killing activity of macrophages. The antimycobacterial effect was associated with the inhibition of potassium and calcium channels, which led to a decrease in pH in the phagolysosome, activation of hydrolases, and subsequent destruction of M. tuberculosis cells (Rodrigues et al., 2020). The levorotatory form showed better antibacterial activity, both in vitro and in vivo; racemic thioridazine was found to reduce the ability of Gram-positive and Gram-negative bacteria to invade cell lines (Foletto et al., 2021a). However, care should be taken to minimize its negative effects on the central nervous system and cardiotoxicity. Hence, there is currently considerable interest in identifying suitable thioridazine analogues or changing the form of the drug, e.g., encapsulation of the drug in nanoparticles (Rodrigues et al., 2020). Currently, research on the repositioning of antipsychotic drugs in the treatment of infectious diseases is in the preclinical phase.

The most commonly prescribed antidepressants include selective serotonin reuptake inhibitors (SSRIs) and tricyclic antidepressants (TCAs). They improve mood and anxiety disorders by inhibiting the transporters responsible for the reuptake of norepinephrine and serotonin. Currently, antidepressants are typically used to treat neuropathic pain in oncological patients. Studies in animal models indicate their analgesic effect is associated with their potential to achieve high noradrenaline concentrations through their action on α2-adrenergic receptors. Dopamine and serotonin may also enhance the analgesic effects of norepinephrine. Additionally, TCAs also inhibit the production of the pro-inflammatory cytokines TNF-α, IL-1β, and IL-6 (Asensi-Cantó et al., 2022; Rácz and Spengler, 2023). They can also inhibit cancer cell growth by blocking their molecular pathways. These phenomena support the rationale for further trials on the usage of TCAs in cancer diseases.

Antidepressants, particularly serotonin reuptake inhibitors (SSRIs), have also been recognized as potential candidates for drug repurposing for treating infectious diseases. For example, sertraline has been demonstrated to enhance the activity of fluoroquinolones and aminoglycosides against S. aureus strains, and its antimicrobial effect in combination with gentamicin and erythromycin, has also been evaluated against P. aeruginosa and E. coli. Sertraline has also shown antibacterial activity against Helicobacter pylori strains in a concentration-dependent manner, as well as possible synergism with amoxicillin, clarithromycin, tetracycline, and metronidazole, used to eradicate H. pylori. The potential mechanism could involve the inhibition of bacterial protein translation and interference with bacterial efflux pumps (Barbarossa et al., 2022). In another study, sertraline increased the effectiveness of polymyxin B against strains of other Gram-negative species such as A. baumannii, E. coli, and K. pneumoniae (Otto et al., 2019), as well as against strains of Enterococcus spp. resistant to vancomycin (Foletto et al., 2021a). The bactericidal effect of sertraline against the reference strains S. aureus, E. faecalis, B. cereus, and E. coli was found to be further enhanced by combining it with disulfiram, used in the treatment of alcoholism. Disulfiram was metabolized by bacterial cells to diethyldithiocarbamate (DDTC), which has antibacterial properties. Additionally, disulfiram has a proteolytic effect due to its ability to chelate ions (Serafin et al., 2020). Clinical trials also included combination therapy of fluconazole and sertraline in the treatment of early disseminated cryptococcal infection (NCT03002012). However, when high doses of sertraline were used, the clinical trial was terminated due to high rate of adverse events (Boulware et al., 2020). In vitro studies have demonstrated synergistic and additive effects of SSRIs in combination with azoles. Sertraline had the best antifungal activity against Cryptococcus spp.; it was believed to act by damaging the mitochondrial membrane and increasing the production of reactive oxygen species, leading to apoptosis (da Silva et al., 2023).

In turn, fluoxetine showed activity against MRSA strains, vancomycin-resistant Enterococcus spp. strains, and A. baumannii strains, which was probably caused by changes in the integrity of bacterial plasma membranes and damage to their DNA, leading to bacterial cell death (Foletto et al., 2020; Foletto et al., 2021a; Foletto et al., 2021b). Both fluoxetine and paroxetine showed improved efficacy in combination with ciprofloxacin against both Gram-negative and Gram-positive microorganisms, compared to ciprofloxacin alone. When the antidepressant was combined with this fluoroquinolone, its potency against MDR-resistant strains of E. coli, A. baumannii, K. pneumoniae, and E. faecium was eightfold increased (Foletto et al., 2020; Foletto et al., 2021b). SSRIs can affect a number of processes regulating the biosynthesis of products important for microorganisms, regardless of absorption into bacterial cells. The mechanism of action may also be based on the inhibition of bacterial efflux pumps (de Sousa et al., 2018; Foletto et al., 2020; Foletto et al., 2021a) or on disturbing bacterial cell wall synthesis and preventing bacterial cell division (Basha et al., 2018). Moreover, fluoxetine affected plasma membrane exopolysaccharides integrity and induced DNA damage, which may lead to bacterial cell apoptosis (Neto et al., 2019; Foletto et al., 2021b).

In turn, amitriptyline, a TCA, had antibacterial activity against carbapenemase-producing strains of K. pneumoniae. A synergistic effect was also obtained when combined with colistin, i.e., the “last resort” antibiotic, and tetracyclines (Barbarossa et al., 2022; Ugurel and Turgut-Balik, 2023).

Valproic acid, used in the treatment of epilepsy and bipolar disorders, stimulates the formation of autophagosomes in vitro. Its has been found to enhance the clinical effects of isoniazid and rifampicin in the treatment of tuberculosis, as demonstrated in studies on human cell lines. The antimycobacterial activity of valproic acid may result from the ability to inhibit succinic semialdehyde dehydrogenase, associated with the process of aerobic respiration. Valproic acid also influences the metabolism of fats, thus regulating the fluidity of cell membranes, and reduce the amount of substrate for the production of prostaglandins (Rodrigues et al., 2020). It is currently also the subject of several clinical trials regarding its effectiveness in the treatment of neuropathic pain or anticancer therapy (NCT01928849) (Caponigro et al., 2016; Iannelli et al., 2020).

Entacapone and tolcapone are able to reversibly inhibit catechol-O-methyltransferase (COMT), and are hence used in the supportive treatment of Parkinson’s disease. These drugs have also shown antituberculosis activity (Maitra et al., 2015; Beklen et al., 2021). The possible mechanism of action against M. tuberculosis strains might be based on their ability to inhibit the synthesis of mycolic acid: a compound necessary for the construction of the mycobacterial cell wall. Its loss leads to the death of bacterial cells (Maitra et al., 2015; Sharma et al., 2023). Unlike isoniazid, entacapone and tolcapone do not require enzymatic activation, so there is no possibility of mutations that can develop resistance (Maitra et al., 2015).

Memantine, a drug used to treat Alzheimer’s disease, has also shown antibacterial properties. It acts by inhibiting N-methyl-d-aspartate (NMDA) receptors in the central nervous system (Johnson and Kotermanski, 2006). Moreover, the discovery of NMDA receptors in non-neuronal tissues, such as the heart, lungs, and kidneys, suggests it may have value across a broader therapeutic spectrum (Zakariaa et al., 2023). Memantine, used in combination with ampicillin, blocked the inflammatory response to bacterial infection caused by E. coli. Studies indicate that memantine affects the α7 nAChR receptor: an inflammation regulator also controlled by bacterial cells. It also reduces the intracellular survival of bacteria, both during bacteremia and in the later phase of meningitis caused by E. coli. Memantine may make it more difficult for the pathogen to penetrate the blood-brain barrier, as evidenced by studies in animal models. Its ability to inhibit the development of meningitis is correlated with the degree of bacteremia development. The proposed doses of this drug showed neuroprotective properties and did not have a toxic effect on human cells (Yu et al., 2015).

The mechanisms of action of antibacterial drugs used in neurological diseases and psychiatry are presented in Figure 6 (Johnson and Kotermanski, 2006; Marchi et al., 2015; Caponigro et al., 2016; Basha et al., 2018; de Sousa et al., 2018; Saputo et al., 2018; Neto et al., 2019; Foletto et al., 2020; Beklen et al., 2021; Maitre et al., 2022).

One of the antidiabetic drugs that inhibit the growth of bacteria is metformin, for which the possibility of repositioning is being investigated in many indications (Gadducci et al., 2016; Matsuoka et al., 2021; Agostini et al., 2022). While metformin has remained the first-line medication to treat type 2 diabetes mellitus (T2DM), its mechanisms of action are complex and not fully understood. The molecule has been recognized to act through activated protein kinase (AMPK)-dependent and AMPK-independent mechanisms in the liver, where it controls hepatic glucose production. The current understanding of the molecular mechanisms of metformin action focuses on the other sites of its pharmacological activity, and consequently, recent years have brought an increasing interest to repurpose metformin for the treatment of cancer, age-related diseases, inflammatory diseases or COVID-19 (Foretz et al., 2023). Metformin has also been successfully repositioned in the treatment of polycystic ovary syndrome.

The use of metformin and Triton X-100 allowed for a reduction in cell viability and a reduction in the virulence potential of E. faecalis (Barbarossa et al., 2022). It has been suggested that the antibacterial effect may be related to the rupture of the inner bacterial membrane (Foletto et al., 2021a). In vivo studies also found that metformin increases phagocytosis by macrophages in the case of E. coli infection and reduces the severity of the disease in the case of M. tuberculosis infection (Brown, 2015). It has also been shown that in the case of tuberculosis, the use of metformin inhibits cell necrosis and contributes to tissue regeneration (Guler and Brombacher, 2015). Metformin also promotes autophagy in infected macrophages and limits the development of mycobacteria by positively influencing the production of reactive oxygen species (Vyas et al., 2022). For this reason, the molecule is currently in clinical trials for the treatment of tuberculosis (NCT05215990, NCT04930744). These are phase 1 and phase 2 interventional studies aimed at assessing whether metformin will have an impact on lung damage and the duration and effectiveness of therapy in tuberculosis. Other studies are ongoing to assess the effect of metformin on mortality in patients with and without diabetes and on inflammatory markers in sepsis and septic shock (NCT05572060, pre-recruitment; NCT06181422; pre-recruitment; NCT05979038, in the recruitment phase—phase 2 and 3 clinical trials).

Acarbose, which inhibits α-glucosidase activity in the small intestine, also has many additional effects beyond its effectiveness in diabetes. In vitro studies have shown that it reduces the inflammation, oxidative stress and platelet activation observed in the course of atherosclerosis (Chan et al., 2016). In in vitro studies, acarbose showed activity against M. tuberculosis: its addition allowed the doses of isoniazid and ethambutol to be halved (Sharma et al., 2023). Additionally, at high concentrations, acarbose was able to inhibit biofilm formation by M. tuberculosis when combined with ethambutol and isoniazid (Kumar et al., 2019b). Similarly, it was found to be effective against respiratory infections caused by P. aeruginosa strains in a type 2 in vitro diabetes model; treatment anti-inflammatory and antimicrobial effects and reduced mortality (Liu et al., 2023).

Statins are a group of drugs used in the treatment of hypercholesterolemia and in the prevention of atherosclerosis. They are responsible for inhibiting the enzyme hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase which is involved in the synthesis of cholesterol in the liver (Foletto et al., 2021a). In recent years, HMG-CoA reductase inhibitors (HMGRI, statins) have emerged as the most important class of lipid-lowering agents. Clinical trials have confirmed the beneficial effects of statins in cardiovascular disorders, in primary and secondary prevention settings, and in asymptomatic subjects with a high cardiovascular risk (Jasinska et al., 2007; Jiang et al., 2021). They are prescribed, among others, after myocardial infarction and ischemic stroke, and in the treatment of atherosclerosis or coronary artery diseases (Murphy et al., 2020). It is well-known that statin pleiotropy provides various beneficial effects in addition to their lipid-lowering properties, such as improved endothelial dysfunction and better nitric oxide bioavailability; treatment also has antioxidant effects, anti-inflammatory and immunomodulatory properties, and has been found to stabilize atherosclerotic plaques and inhibit cardiac hypertrophy. In addition, statins have demonstrated anti-tumor properties, which have attracted particular attention for repurposing (Jasinska et al., 2007; Rohilla et al., 2016; Jiang et al., 2021). Some studies have shown HMGRI to have potential efficacy in dementia and Alzheimer’s disease, non-alcoholic fatty liver disease, and due to their immunomodulatory and antioxidant properties, also in rheumatoid arthritis (Murphy et al., 2020; Aminifar et al., 2023).

A wealth of evidence shows that people taking statins could have a lower risk of bacterial infections and better survival during infection. They are less exposed to community-acquired blood infections caused by S. aureus strains. Additionally, the risk of developing sepsis was also lower. In vivo studies have shown that simvastatin treatment is beneficial in lung infections caused by S. aureus strains: it lowered inflammatory marker levels and reduced mortality in animal models (Evans and McDowell, 2021). It has been proposed that the drugs exert their antibacterial activity by promoting apoptosis, and the mechanism of action is unrelated to the inhibition of HMG-CoA reductase (Foletto et al., 2021a).

Antibacterial effects were also demonstrated by atorvastatin and pitavastatin. It has been proposed that they act by breaking down the structures of teichoic acid and reducing the number of alanine residues on the surface of Gram-positive bacteria cells, which would reduce the ability of bacterial cells to form a biofilm (Barbarossa et al., 2022). Atorvastatin, lovastatin, and simvastatin have demonstrated significant inhibition of bacterial growth in biofilms, including S. mutans (Saputo et al., 2018).

Simvastatin also showed synergy of action with silver ions against MRSA strains and against E. coli producing β-lactamases with an extended substrate spectrum. Treatment resulted in distorted and lysed bacterial cells associated with a change in membrane permeability (Barbarossa et al., 2022). In an animal model of diabetes, simvastatin also accelerated wound healing and angiogenesis, influencing the control of inflammation by limiting the production of TNF-α and IL-6. Therefore, it may be an adjunct drug in the treatment of skin infections caused by MRSA strains (Thangamani et al., 2015). Atorvastatin was similarly active against both Gram-positive bacteria (S. aureus) and Gram-negative bacteria (A. baumannii, E. aerogenes, E. coli) (Foletto et al., 2021a). Atorvastatin is currently involved in clinical trials for the treatment of bronchiectasis (NCT01299194), a chronic lung disease characterized by thick secretions and frequent respiratory infections. In most patients, it leads to chronic bacterial colonization.

M. tuberculosis can use cholesterol contained in host macrophages for infection and its own survival (Su et al., 2021). Therefore, the presence of higher cholesterol levels may be a predisposing factor to tuberculosis, and reducing its level may help limit the entry of bacteria to macrophages. Simvastatin, in combination with rifampicin, isoniazid, and pyrazinamide, has been shown to be effective against infections caused by M. tuberculosis. These combinations show increased mycobacterial killing, a decrease in the number of colony-forming units in the lungs, and a shorter time to obtain a pure culture. Additionally, the inflammatory process was also found to be regulated by increased secretion of the cytokines IL-12, IL-1β, and IL-10 (Sharma et al., 2023). In vivo models have shown that statins shorten the cure time for tuberculosis and have a beneficial effect on changes in the lungs. They also have the ability to inhibit T cell activation induced by M. tuberculosis antigens. Additionally, their use significantly reduces the rate of tuberculosis recurrence by almost 50%. As a consequence, several clinical trials are currently being conducted on the effectiveness of statins as an adjuvant therapy in tuberculosis (NCT04504851, NCT04721795, completed, no trial results; NCT06199921, in the recruitment phase). Atorvastatin is also being considered for treatment to reduce inflammation after TB treatment (NCT04147286, in the recruitment phase). These clinical trials on the use of statins in the treatment of tuberculosis are currently in phase 2 and 3 of clinical trials.

The antibacterial mechanism of antidiabetic anh hypolipemic drugs is shown in Figure 8 (Brown, 2015; Brindha et al., 2016; Guerra-De-Blas et al., 2019; Evans and McDowell, 2021; Vyas et al., 2022).