TY - JOUR
T1 - On the mechanism of berberine-INF55 (5-Nitro-2-phenylindole) hybrid antibacterials
AU - Dolla, Naveen K.
AU - Chen, Chao
AU - Larkins-Ford, Jonah
AU - Rajamuthiah, Rajmohan
AU - Jagadeesan, Sakthimala
AU - Conery, Annie L.
AU - Ausubel, Frederick M.
AU - Mylonakis, Eleftherios
AU - Bremner, John B.
AU - Lewis, Kim
AU - Kelso, Michael J.
N1 - Funding Information:
We gratefully acknowledge the US National Institutes of Health (grant numbers R01 AI076372 and P01 AI083214) for funding this work and we thank all of the universities involved for their support.
Publisher Copyright:
© CSIRO 2014.
PY - 2014
Y1 - 2014
N2 - 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.
AB - 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.
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U2 - 10.1071/CH14426
DO - 10.1071/CH14426
M3 - Article
AN - SCOPUS:84907983764
VL - 67
SP - 1471
EP - 1480
JO - Australian Journal of Chemistry
JF - Australian Journal of Chemistry
SN - 0004-9425
IS - 10
ER -