On the Mechanism of Berberine–INF55 (5-Nitro-2-phenylindole) Hybrid Antibacterials

Abstract

Berberine–INF55 hybrids are a promising class of antibacterials that combine berberine and the NorA multidrug resistance pump inhibitor INF55 (5-nitro-2-phenylindole) together in one molecule via a chemically stable linkage. Previous studies demonstrated the potential of these compounds for countering efflux-mediated antibacterial drug resistance but they didn’t establish whether the compounds function as originally intended, i.e. with the berberine moiety providing antibacterial activity and the attached INF55 component independently blocking multidrug resistance pumps, thereby enhancing the activity of berberine by reducing its efflux. We hypothesised that if the proposed mechanism is correct, then hybrids carrying more potent INF55 pump inhibitor structures should show enhanced antibacterial effects relative to those bearing weaker inhibitors. Two INF55 analogues showing graded reductions in NorA inhibitory activity compared with INF55 were identified and their corresponding berberine–INF55 hybrids carrying equivalent INF55 inhibitor structures synthesised. Multiple assays comparing the antibacterial effects of the hybrids and their corresponding berberine–INF55 analogue combinations showed that the three hybrids all show very similar activities, leading us to conclude that the antibacterial mechanism(s) of berberine–INF55 hybrids is different from berberine–INF55 combinations.

Exploration of Biaryl Carboxylic Acids as Proton Shuttles for the Selective Functionalization of Indole C–H Bonds

“…The product was isolated by column chromatography (PE:EA = 5:1) as a light yellow solid (48.4 mg, 68%). Spectral data is consistent with previous reports …”

Efflux pump inhibitors of clinically relevant multidrug resistant bacteria

“…In addition, structural simplification of the indole moiety turned out to be unfavorable for the antibacterial activity of hybrids, although it was shown that the indole nucleus is not necessary for NorA EPI . One may quickly conclude that berberine‐INF55 hybrids elicit their antibacterial effects through the combination of activities of two functionally distinct components (antibacterially active berberine and NorA inhibitor INF55), but a study suggests that the exact mechanism of action, in this case, differs from that when berberine is co‐administered with INF55‐based EPIs …”

“…190 One may quickly conclude that berberine-INF55 hybrids elicit their antibacterial effects through the combination of activities of two functionally distinct components (antibacterially active berberine and NorA inhibitor INF55), but a study suggests that the exact mechanism of action, in this case, differs from that when berberine is co-administered with INF55-based EPIs. 191 To date, several potent indole-based NorA inhibitors were discovered and optimized, but their efficacy still needs to be evaluated in clinical settings.…”

13-(2-Methylbenzyl) Berberine Is a More Potent Inhibitor of MexXY-Dependent Aminoglycoside Resistance than Berberine

“…Various derivatives of berberine have been developed and studied for their anti-hyperglycemic, anti-cancer, anti-inflammatory, anti-Alzheimer's disease and anti-microbial activities [19]. Derivatives with multidrug resistance pump inhibitory activity against Staphylococcus aureus [20] and that reduce fluconazole resistance against Candida albicans [21] have been reported. In addition, quaternary ammonium compounds inhibit the biofilm formation in P. aeruginosa and C. albicans have been reported [22].…”