In the clinic, vancomycin and polymyxins (including polymyxin B and E, also called colistin) are commonly employed as antibacterial drugs against MDR Gram-negative and Gram-positive bacteria, respectively [90]. The emergence of polymyxin- and vancomycin-resistant bacteria has posed a huge challenge and medical burden.

The well-accepted primary mechanism of action of polymyxins is through spatially displacing the cations (e.g., Ca²⁺ and Mg²⁺) in the Gram-negative outer membrane and binding to the lipid A component of the lipopolysaccharide (LPS), subsequently disrupting the stability of both the outer and inner membranes, ultimately leading to bacterial cell lysis [91]. Recent studies also indicated that polymyxins can also induce the production of excessive ROS (i.e., OH^•) in bacterial cells, leading to oxidative stress-dependent cell death [92]. Polymyxin B in combination with curcumin showed a marked synergetic effect against polymyxin-susceptible and -resistant Gram-positive (e.g., Enterococcus, S. aureus, and Streptococcus) and Gram-negative (e.g., A. baumannii, E. coli, P. aeruginosa, and S. maltophilia) bacterial isolates associated isolated from traumatic wound infections [32]. This synergistic effect may be due to curcumin’s ability to permeabilize the outer membrane, which facilitates the entry of the secondary agent to enter the bacterial cells and cause cell death [24]. In addition, this synergistic effect could be attributed to the inhibitory effect of curcumin on the activities of efflux pumps [9,24]. Curcumin and polymyxin combination treatment for bacterial infections may have another advantage, i.e., significant improvement in the therapeutic index of polymyxins by additionally inhibiting polymyxin-induced cytotoxicity, neurotoxicity, and nephrotoxicity, which is beyond antibacterial activity [93]. This combination may have a powerful application in clinical practice and warrants clinical trials.

Vancomycin is a glycopeptide antibiotic that inhibits a specific step in the synthesis of the peptidoglycan layer in Gram-positive bacteria. It has been reported that curcumin combined with vancomycin showed a synergistic effect against MDR clinical K. pneumoniae isolates [94]. This potential mechanism may be dependent on the synergistic effect of cell membrane permeability [94]. Moreover, curcumin could also attenuate vancomycin-induced nephrotoxicity by inhibiting oxidative stress and the inflammation response in a rat model [94].

β-lactam antibiotics are the most widely used antibacterial agents worldwide. β-lactamases confer significant antibiotic resistance to their bacterial hosts by hydrolyzing the amide bond of the four-membered β-lactam ring of β-lactam antibiotics, which include four classes of drugs, i.e., penams (penicillins), cephems (cephalosporins), monobactams, and carbapenems [95]. It has reported that a curcumin and meropenem combination displayed markedly synergistic or additive effects against antibiotic-susceptible and -resistant Gram-positive (E. faecalis) and carbapenem-associated MDR A. baumannii, P. aeruginosa, and K. pneumoniae isolates via the observation of MICs [86]. A report by Yadav et al., showed that a water-soluble curcumin derivative could reverse meropenem resistance by targeting the activity of carbapenemases and the AcrAB-TolC multidrug efflux pump system [96]. Mun et al. showed that a curcumin combination with oxacillin and ampicillin exhibited a marked synergistic effect against S. aureus ATCC (American Type Culture Collection) 25,923 (methicillin-sensitive strain) [97]. Similarly, in another study, BDMC in combination with oxacillin showed a marked synergistic effect against S. aureus ATCC 33,591 (methicillin-resistant strain) and clinical MRSA isolates [98]. The potential mechanism may be dependent on the expression of the mecA gene that encodes penicillin-binding protein 2a (PBP2a), which governs the resistance of MRSA isolates to β-lactam antibiotics [98]. Sasidharan et al. found that curcumin in combination with third-generation cephalosporins (e.g., cefaclor, cefodizime, and cefotaxime) showed marked synergistic effect against S. aureus, B. subtilis, and E. coli, which are also associated with infectious diarrhea [87]. There was no increased toxic effects between these combinations [87]. These results indicated curcumin and cephalosporin combination are promising therapeutic options for infectious diarrhea disease.

Aminoglycosides are potent, broad-spectrum antibiotics that act through inhibition of protein synthesis by irreversibly binding to 30S ribosomal subunits [99]. A report by Teow et al., stated that curcumin in combination with two aminoglycoside antibiotics (e.g., amikacin and gentamicin) showed a powerful synergistic effect against S. aureus strains, and these synergistic effects were stronger than that of curcumin in combination with ciprofloxacin [100]. Notably, this difference in synergistic effect may be related to the difference in the primary targets between quinolone and aminoglycosides against bacteria [101]. The potential action mechanism is related to the inhibition of biofilm formation, which was evident by the significant inhibition of their combination of the swarming motilities and the mRNA expression of several key QS regulatory genes (e.g., lasI, lasR, rhlI, and rhlR) [100]. In addition, it has been reported that curcumin can also attenuate gentamicin-induced nephrotoxicity and neurotoxicity by inhibiting oxidative stress and cell apoptosis in a rat model [102]. Therefore, the combination between curcumin and aminoglycosides can not only improve the antibacterial effectiveness but can also decrease the toxic effects of gentamicin.

Azithromycin is a macrolide antibiotic, which can exhibit a good antibacterial effect by inhibiting bacterial protein synthesis, quorum-sensing, and the formation of biofilms. In clinical practice, azithromycin has been used in treating respiratory, urogenital, dermal, and other bacterial infections [103]. Bahari et al., found that curcumin in combination with azithromycin showed a synergistic effect against P. aeruginosa PAO1, and the value of FICI was 0.25 [100]. The potential action mechanism may be similar to the above-mentioned combination of curcumin and gentamicin [100]. Erythromycin is in a class of medications called macrolide antibiotics. The action mechanism involves the blockade of bacterial growth. In a rat model, oral administration of curcumin (50 mg/kg) and erythromycin (20 mg/kg) significantly inhibited the growth of MRSA isolates in bone tissue compared to either administered alone [11]. The curcumin and erythromycin combination also significantly alleviated bone infection and the inflammatory response [11].

There was a marked synergistic effect in curcumin combination with two quinolone antibiotics (e.g., ciprofloxacin and norfloxacin) against the S. aureus ATCC 33,591 strain and clinical MRSA isolates [97]. On the contrary, curcumin treatment reduced the antimicrobial activity of ciprofloxacin against Salmonella typhimurium and Salmonella typhi [97]. This may be related to the antioxidant property of curcumin and its inhibition of the expression of interferon γ (IFNγ) in vitro and in a mouse model [97].

Berberine is a benzylisoquinoline alkaloid compound and has antimicrobial properties against both Gram-negative and Gram-positive bacteria [104]. Berberine has been widely used in traditional Chinese and native American medicines. FtsZ protein is an important target of berberine in inhibiting bacterial division [105]. Interesting, co-encapsulation of berberine and curcumin in liposomes decreased their MICs against MRSA by 87% and 96%, respectively, as compared to their free forms, with an FICI of 0.13, indicating a synergistic effect [88]. However, the synergistic effect in their combination in native form was not detected. In addition, co-treatment of berberine and curcumin in liposomes also significantly improved intracellular infection and the inflammation response in macrophages following MRSA infection. Mechanically, the synergistic effect between curcumin and berberine is partly dependent on the inhibition of biofilm formation and improvement of their solubilities [88]. Additionally, similar to curcumin, berberine is also an FtsZ inhibitor and inhibits bacterial cell division [104]. Therefore, this synergistic effect between curcumin and berberine may also be partly dependent on the inhibition of FtsZ assembly.

Epigallocatechin-3-gallate (EGCG) is a polyphenol found in green tea, which, similar to curcumin, has been linked with health benefits and has significant antimicrobial activity against some MDR pathogens, including MDR S. maltophilia, A. baumannii, and S. aureus [106]. In vitro, it has been found that curcumin in combination with EGCG exhibited a marked synergistic effect against MDR A. baumannii [107]. A possible explanation for the synergy between curcumin and EGCG could be disruption of the outer membrane and facilitation of curcumin to enter bacterial cells [108]. In another study, it was suggested that inhibition of acylhomoserine lactone-mediated biofilm formation may contribute to this synergistic effect, and investigations of precise mechanisms are still required [109].