Flavonoids are compounds of some widely distributed plants and are found in photosynthetic cells, which exist broadly within the plant kingdom and in almost all parts of the plant (Havsteen, 1983). Baicalein and baicalin in the root of Scutellaria baicalensis Georgi, luteolin in the root and stem of Reseda odorata L., and quercetin in the flower and leaf of Camellia sinensis (L.) Kuntze are all flavonoids. For centuries, preparations containing flavonoids as the key physiologically active ingredients have been used by clinicians to treat human diseases. It is reported that flavonoids have anti-inflammatory and antibacterial effects, whilst potentially having antiviral, antioxidant and free radical scavenging abilities (Kumar and Pandey, 2013). Researchers have also actively investigated the antibacterial effects of flavonoids in combination with antibiotics.

Mai Fujita et al. (2005) demonstrated that the combination of baicalein with tetracycline and β-lactam antibiotics significantly reduced the MIC of MRSA such that it played an antibacterial role. When baicalein and ciprofloxacin were combined to treat MRSA infection, 12 of the 20 drug-resistant strains had FICI≤0.5, which mainly inhibited the efflux of ciprofloxacin by suppressing the efflux pump, thereby exerting a synergistic anti-MRSA effect (Chan et al., 2011). The main mechanism of the combination of active ingredients of TCM and antibiotics is shown in Figure 2. Qian et al. (2015) also found that the combined application of baicalein and penicillin can resist penicillinase-producing MRSA or S. aureus infection. When the concentration of baicalein increased from 8 μg/ml to 32 μg/ml, the MIC of penicillin decreased from 64 μg/ml to 4 μg/ml, significantly improving the resistant bacteria’s susceptibility to penicillin. Recent studies have demonstrated that linezolid and baicalein can inhibit biofilm formation in vivo to play an anti-MRSA role (Liu T. et al., 2020). Baicalin has similar effects to baicalein, and if Baicalin is used in combination with oxytetracycline and tetracycline, it can resist S. aureus infection, while in combination with β-lactam antibiotics, it yields anti-MRSA activity (Iain and Liu, 2000; Novy et al., 2011).

Usman Amin et al. (2016) demonstrated synergistic effects of luteolin and quercetin combined with ceftriaxone and imipenem against MRSA. In addition, luteolin combined with ampicillin, oxacillin, and gentamicin can synergically enhance the antibacterial action of aminoglycosides and β-lactam antibiotics against MRSA. The FICI of the combination of 1 2 MIC luteolin and 1 2 MIC antibiotics against MRSA ATCC 33591 for most strains was 0.125–0.562, and these combinations did not show additive or antagonistic effects (Joung et al., 2016). As well as inhibiting MRSA, luteolin can synergize with amoxicillin to reverse the resistance of amoxicillin-resistant E. coli and can fight Streptococcus pyogenes infection when combined with ceftazidime. Quercetin can also combat S. pyogenes combined with ceftazidime, where the FICIs of luteolin and quercetin paired with ceftazidime were 0.37 and 0.27, respectively (Eumkeb et al., 2012b; Siriwong et al., 2015). Siriwong et al. (2016) also demonstrated that quercetin with amoxicillin could reverse the resistance of amoxicillin-resistant Staphylococcus epidermidis. In addition, quercetin with ciprofloxacin, tetracycline, and erythromycin has an antibacterial effect on S. aureus, including MRSA. In the time-kill curves test, quercetin with tetracycline reduced the cell viability of resistant E. coli strains by more than eight times within 24 h compared with the drug group alone and had a FICI ≤0.5 (Abreu et al., 2016; Qu et al., 2019). Compared with other antibiotics, researchers found that ¼ MIC, 1 8 MIC quercetin combined with tobramycin and amikacin has potential systematic antibacterial activity against multidrug-resistant Pseudomonas aeruginosa (Vipin et al., 2020). Pal and Tripathi (Pal and Tripathi, 2019; 2020) reported that quercetin and meropenem had synergistic antibacterial effects on carbapenem-resistant P. aeruginosa, A. baumannii, E. coli, and K. pneumoniae, with FICI values of 0.18–0.50, 0.16–0.37, 0.187–0.375, and 0.093–0.500, respectively, which can not only significantly kill bacteria but also may reverse drug resistance.

It has been reported (Kang et al., 2011; Cai et al., 2018; Vivekanandan et al., 2018) that silibinin, an extract of Silybum marianum (L.) Gaertn., has anti-MRSA activity when combined with oxacillin or ampicillin. Another extract, silymarin, can improve the toxicity of linezolid and synergistic anti-MRSA infection, while a high concentration silibinin with kanamycin can inhibit the growth of S. aureus. Pimchan et al. (2017) demonstrated a synergistic effect between α-mangostin and ceftazidime in A. baumannii. The FICI of the combination of α-mangiferin and oxacillin against oxacillin-resistant Staphylococcus saprophyticus was 0.37. The number of bacterial colonies decreased by the combination of 2 μg/ml α-mangostin and 16 μg/ml oxacillin, and in the time-kill curves test ≥2 log10 cfu/ml also verified the synergy. When α-mangostin is combined with gentamicin and vancomycin hydrochloride, it can help inhibit vancomycin-resistant Enterococci (VRE) and MRSA infection, respectively (Sakagami et al., 2005; Phitaktim et al., 2016). Table 1 lists the antibacterial effects of flavonoids combined with antibiotics.

Alkaloids are components of botanical drugs and are widely distributed in nature. They are organic compounds with biological activity and are present within a wide range of plants, bacteria, and fungi (Qiu et al., 2014). Berberine is extracted from Berberis vulgaris L., total alkaloids from Sophora alopecuroides L., and tetrandrine from Stephania tetrandra S. Moore are common alkaloids. Several clinical studies have reported that alkaloids have anti-inflammatory (Souza et al., 2020), antibacterial activities (Liu Y. et al., 2020) and antiviral (Gorpenchenko et al., 2019) pharmacological effects. Studies have shown that these alkaloid compounds are important in enhancing antibiotic effects for treating infections (Cushnie et al., 2014). In recent years, researchers have explored cooperative applications of alkaloids and antibiotics to fight against bacterial resistance.

Hyeon-Hee et al. (2005) showed the anti-MRSA effect of berberine. The FICI of berberine combined with ampicillin (0.625) had an additive effect, whereas if it joined with oxacillin (0.5) it had a synergistic effect. Some scholars have found that berberine combined with azithromycin has a synergistic antibacterial effect on MRSA and P. aeruginosa, and if it paired with levofloxacin, it could resist MRSA infection. The combination of ¼ MIC berberine and 1 8 MIC imipenem had a synergistic antibacterial effect on carbapenems resistant P. aeruginosa with a FICI of 0.375. In addition, berberine can increase the antibacterial activity of gentamicin and other aminoglycoside antibiotics against P. aeruginosa and reverse the resistance of antibacterial drugs. When berberine was combined with linezolid, cefoxitin, and erythromycin, the synergistic effect was significant in coagulase-negative staphylococcus (Zuo et al., 2012; Wojtyczka et al., 2014; Morita et al., 2016; Li et al., 2017; Su and Wang, 2018). Although the FICI of berberine and ciprofloxacin against multidrug-resistant Salmonella and K. pneumoniae were between 0.375 and 1, the time-kill curves test confirmed the synergistic antibacterial effect of the combination (Zhou et al., 2016; Shi et al., 2018). Studies have shown that berberine and fluconazole can be combined to resist drug-resistant Candida albicans and fluconazole-resistant Candida tropicalis. Berberine can increase the biosynthesis of ergosterol, making it resistant to C. albicans. The effect of fluconazole on ergosterol can eliminate the resistance of berberine and synergise with berberine against drug-resistant C. albicans. Berberine and fluconazole also synergise against fluconazole-resistant Candida tropicalis by inhibiting efflux pumps (Shi et al., 2017; Xu et al., 2017). Liang et al. (2014) showed that an isoquinoline alkaloid may be extracted from Berberis vulgaris L. and other plants. The combination of berberine chloride and fusidic acid has shown a synergistic antibacterial effect on seven clinically isolated MRSA strains, with most significant inhibitions on two highly resistant strains, 4,806 and 7,155-1, and their FICIs were 0.19 and 0.38, respectively. Berberine chloride can increase the susceptibility of multidrug-resistant A. baumannii to tigecycline, sulbactam, meropenem, and ciprofloxacin to facilitate a more effective antibacterial role (Li et al., 2021). When berberine chloride combined with penicillin, clindamycin, and erythromycin, can also significantly inhibit the growth of Streptococcus oralis in a dose-dependent manner. Further, when combined with vancomycin, it can greatly inhibit the growth and motor capacity of Clostridium difficile, and can synergistically inhibit drug-resistant C. albicans when paired with fluconazole (Dziedzic et al., 2015; Wultanska et al., 2020; Yong et al., 2020).

Khameneh et al. (2015) demonstrated that the co-application of piperine and gentamicin nanoliposomes on MRSA had a significant synergistic antibacterial effect. Some researchers have shown that low-dose total alkaloids of Sophora alopecuroides L. and ciprofloxacin have synergistic antibacterial activity against multidrug-resistant E. coli. Total alkalids can enhance bacterial susceptibility to ciprofloxacin and cooperate with cefotaxime and ceftazidime against extended-spectrum β-lactamase (ESBL)-producing E. coli infection (Zhou et al., 2013; Pourahmad Jaktaji and Mohammadi, 2018). In time-kill curve tests, Zhang et al. (2010) showed that the combined application of 30 μg/ml tetrandrine and ketoconazole on drug-resistant Candida had synergistic antibacterial effects in vitro and in vivo but had no bactericidal effect. Tetrandrine and cefazolin in bisbenzylisoquinoline alkaloids presented a considerable synergistic effects against 90% of 10 clinically isolated MRSA strains, with the FICI between 0.188 and 0.625, while demethyltetrandrine and cefazolin had respective additive activities against 50% and 90% of tested MRSA strains, with the FICI ranging from 1.5 to 2.0 (Zuo et al., 2011). Another compound from TCM, called sanguinarine, can restore antibacterial activity of ampicillin, oxacillin, norfloxacin, and ciprofloxacin to treat MRSA by inhibiting the growth of drug-resistant bacteria (Obiang-Obounou et al., 2011). Table 2 lists the antibacterial effects of the above alkaloids combined with antibiotics.

Phenolic compounds are some of the most diverse bioactive secondary metabolites in medicinal plants. They may also be a part of or the main component that contributes to a plants’ bioactivity, with high antibacterial potential (Pinheiro et al., 2018). Phenolic compounds include: epigallocatechin gallate (EGCg), magnolol and honokiol, and eugenol, extracted from Camellia sinensis (L.) Kuntze, Magnolia officinalis Rehder & E.H.Wilson, and Syzygium aromaticum (L.) Merr. & L.M.Perry, respectively. Studies have found that they have anti-inflammatory, antibacteria and antioxidant effects (Daglia, 2012). These compounds may also be used to inhibit or kill pathogenic microorganisms (Marino et al., 2001). Researchers have also investigated the application of phenolic compounds with antibacterial drugs in the treatment of bacterial infections.

Hu et al. (Hu et al., 2001; 2002) demonstrated in 2001 that epigallocatechin gallate (EGCg) could be used together with β-lactam antibiotics, such as ampicillin or sulbactam for the treatment of MRSA infection. EGCg can also be combined with carbapenem antibiotics such as imipenem or panipenem in the treatment of MRSA infection, and reverse MRSA resistance. When EGCg is paired with oxytetracycline it has antibacterial effects on MRSA. EGCg at 4 μg/ml showed synergistic and additive effects on six and two clinically tested MRSA strains, respectively, with the FICI from 0.288 to 0.527 (Novy et al., 2013). A study showed that EGCg can further inhibit penicillinase to protect the antibacterial activity of penicillin and ampicillin against penicillinase-producing S. aureus (Zhao et al., 2002). It has been reported (Sudano Roccaro et al., 2004) that 50 μg/ml EGCg ( 1 2 MIC) joined with tetracycline can significantly reduce the MIC of tetracycline against S. aureus and exert an obvious antibacterial effect.

Kim et al. (2015) demonstrated that 10 μg/ml magnolol and 25 μg/ml honokiol combined with oxacillin has synergistic effects on MRSA. This application can increase the susceptibility of β-lactam antibiotics to MRSA. In vivo and in vitro experiments have demonstrated that the survival rate for honokiol combined with fluconazole in the treatment of fluconazole-resistant C. albicans infection reached 100%, compared with 20% for honokiol-treated or control group of mice over a period of 5 days (Jin et al., 2010). Sousa Silveira et al. (2020) found that thymol and tetracycline had an anti-S. aureus effect. In this study, the results of a fumigation bioassay showed that thymol had an obvious toxic effect on Drosophila melanogaster within 48 h of exposure with an EC₅₀ (concentration for 50% of maximal effect) value of 17.96 μg/ml. Another study, showed the combination of mupirocin and thymol can enhance the antibacterial activity of mupirocin against MRSA (Kifer et al., 2016). Hemaiswarya and Doble (2009) found that eugenol combined with β-lactam antibiotics such as vancomycin, ampicillin, or oxacillin, had a synergistic antibacterial effect on Gram-negative bacilli. Some scholars (Wang et al., 2018; Dhara and Tripathi, 2020) showed that eugenol combined with colistin enhanced the antibacterial activity of the antibiotics against colistin-resistant E. coli, while the combination of eugenol with cefotaxime and ciprofloxacin could resist ESBL-producing quinolone-resistant pathogenic Enterobacteria, with FICI ≤0.5. Khan et al. (2019) demonstrated a synergistic effect of low doses (100 μg/ml) of eugenol together with amphotericin B (0.05 μg/ml) against C. albicans, with a FICI of 0.27. However, methyl gallate of Galla Rhois (Rhus chinensis Mill.), or carvacrol and nalidixic acid combination had a synergistic or partial synergistic effect (FICI = 0.31–0.75) on pathogens resistant to nalidixic acid, whereas methyl gallate or carvacrol restored the antibacterial activity of nalidixic acid (Choi et al., 2009).

Bahari et al. (2017) showed that sub-MIC of curcumin combined with azithromycin and gentamicin had a synergistic effect on P. aeruginosa PAO1. Moreover, the combination of sub-MIC curcumin and ceftazidime had a synergistic effect on P. aeruginosa PAO1 with a FICI of 0.26, and its combination with ciprofloxacin had a FICI of an additive effect (Roudashti et al., 2017). Several studies (Kaur et al., 2018; Itzia Azucena et al., 2019; Sundaramoorthy et al., 2020) showed that curcumin itself did not affect bacterial growth, but when combined with ceftazidime could resist enterotoxin E. coli infection. When combined with salicylate and colistin, curcumin could reduce the biological load of colisin-resistant E. coli U3790 and K. pneumoniae BC936. In addition, curcumin has a synergistic antibacterial effect on A. baumannii when paired with colistin. In another study, Wang et al. (Wang et al., 2020) demonstrated that the combination of 1 2 MIC bisdemethoxycurcumin and 1 2 MIC gentamicin had a significant synergistic effect on MRSA and a partial synergistic effect with oxacillin or a β-lactam antibiotic.

Abu El-Wafa et al. (2020) showed that the combination of phenolic extracts of pomegranate (Punica granatum L.) and rosemary (Rosmarinus officinalis L.) with piperacillin, ceftazidime, imipenem, gentamicin, and levofloxacin was effective in treating against P. aeruginosa PS-1 and exhibited a synergistic effect (FICI ≤0.5), which radically reduced the MIC of P. aeruginosa. Liu et al. (2016) found that the combination of salvianolic acid salt in Salvia miltiorrhiza (Salvia miltiorrhiza Bge.) and ampicillin applied to MRSA had the best antibacterial effects, which could also reverse MRSA resistance. Table 3 lists the antibacterial effects of the above phenolic compounds combined with antibiotics.

Quinone compounds in TCM can be divided into four types: benzoquinone, naphthoquinone, phenanthrene quinone, and anthraquinone. Anthraquinone and naphthoquinone are widely used in antibacterial treatment. Anthraquinone compounds from various plants were reported to have antibacterial activity (Novais et al., 2018) and anti-inflammatory, antifungal and antiviral effects (Li and Jiang, 2018). Naphthoquinone and naphthoquinone derivatives (Janeczko et al., 2016) were also reported to have antibacterial activity. Rhein extracted from Rheum palmatum L., resveratrol from the rhizome of Polygonum cuspidatum Sieb. et Zucc., and cryptotanshinone from Salvia miltiorrhiza Bge. are quinones. Quinone compounds in combination with antibiotics have been developed as a new measure for treating antibiotic resistance.

Joung et al. (2012) demonstrated that the FICI of rhein combined with ampicillin or oxacillin for all MRSA strains was 0.28–1 and 0.18–1, respectively and showed a synergistic or partial synergistic effect. Cannatelli et al. (2018) reported that resveratrol had no obvious intrinsic antibacterial activity but displayed synergistic effects with colistin on colistin-resistant Gram-negative bacilli of different species. Resveratrol oxide combined with vancomycin and ciprofloxacin had a synergistic effect on MRSA. It was partially additive or synergistic for the combination of resveratrol oxide with ampicillin, oxacillin, and norfloxacin. These combinations completely inhibited the growth of bacteria after 24 h (Joung et al., 2015). Studies have found that hypericin and β-lactam antibiotics such as oxacillin have anti-MRSA ability (Wang et al., 2019). Cha et al. (2014) demonstrated that cryptotanshinone combined with ampicillin, oxacillin, or vancomycin had synergistic effects on methicillin-resistant and vancomycin-resistant S. aureus and greatly inhibited the growth of bacteria. In addition, cryptotanshinone, together with gentamicin and streptomycin at safe doses (gentamicin ≤12 μg/ml and streptomycin ≤20 μg/ml) had a synergistic antibacterial effect on S. aureus. It reduced the resistance of aminoglycoside antibiotics to drug-resistant S. aureus, while the combination of cryptotanshinone with fosfomycin showed synergistic effect on fosfomycin-sensitive and fosfomycin-resistant S. aureus (FICI, 0.3125–0.375) (Teng et al., 2018; Ruan et al., 2020). Table 4 lists the antibacterial effects of the above quinones in combination with antibiotics.

Lu et al. (2013) demonstrated that sodium new houttuyfonate could be synergistic with cephalosporin, meropenem, oxacillin, and netilmicin against MRSA infection. The median FIC of the checkerboard method was 0.38, 0.38, 0.25, and 0.38, respectively. Several studies (Jiang et al., 2011; Li et al., 2011; Wei et al., 2020) reported that artesunate combined with oxacillin and ampicillin had a synergistic antibacterial effect on MRSA. Combined with β-lactam antibiotics such as ampicillin, artesunate could also inhibit E. coli infection and enhance the antibacterial activity of fluoroquinolones against multidrug-resistant E. coli. The combination of 3-benzylchroman derivatives from the Chinese drug, Caesalpinia sappan L., with the aminoglycoside antibiotic can also be effective against MRSA. Morin, and trans-cinnamaldehyde combined with oxacillin has shown a synergistic effect against MRSA and potential for reversing the drug resistance of MRSA. Magnolia officinalis (Magnolia officinalis Rehder & E.H.Wilson) and Verbena (Verbena officinalis L.) extracts combined with oxacillin have otherwise showed a synergistic effect with partial efficacy against MRSA infection, where the colony number decreased by 3log10 cfu/mL (DPS-1 and DPS-3) after a treatment with a combination of 1 2 MIC morin and 1 2 MIC oxacillin for 24 h (Zuo et al., 2014; Mun et al., 2015; Kuok et al., 2017; Wang et al., 2021). Some scholars (Vazquez et al., 2016; Buommino et al., 2021) demonstrated that the pairing of rosin acid and oxacillin increased the susceptibility of methicillin-resistant Staphylococcus pseudo intermediate to oxacillin. Conversely, carnosic acid and gentamicin had obvious synergistic effects of bactericidal and bacteriostasis on clinical isolates of multidrug-resistant MRSA, while 4 μg/ml gentamicin combined with 4 μg/ml carnosic acid showed a 100% inhibition on bacterial growth. Fatemi et al. (2020) found that methanol extract of Salvia chorassanica (Salvia chorassanica Bunge) and Artemisia khorassanica (Artemisia oliveriana J. Gay ex Besser) synergically enhanced the susceptibility of multidrug-resistant A. baumannii with amikacin and imipenem. In addition, the combination of zingerone and ciprofloxacin significantly inhibited the formation of P. aeruginosa PAO1 biofilm and played an antibacterial role. Stephania suberosa Forman extract (2 mg/ml) in combination with ampicillin (0.15 μg/ml) had a significant effect on the treatment of MRSA infection and significantly reduced the dosage of ampicillin from >512 μg/ml (used alone) to 0.15 μg/ml (combined with the extract) (Kumar et al., 2013; Yothin Teethaisong 2014). Table 5 lists the antibacterial effects of other active ingredients mentioned above in combination with antibiotics.