On the Mechanism of Berberine–INF55 (5-Nitro-2-phenylindole) Hybrid Antibacterials*
Naveen K. Dolla A F , Chao Chen B F , Jonah Larkins-Ford C , Rajmohan Rajamuthiah D , Sakthimala Jagadeesan C E , Annie L. Conery C E , Frederick M. Ausubel C E , Eleftherios Mylonakis D , John B. Bremner A , Kim Lewis B and Michael J. Kelso A GA School of Chemistry, University of Wollongong, Wollongong, NSW 2522, Australia.
B Department of Biology and Antimicrobial Discovery Center, Northeastern University, Boston, MA 02115, USA.
C Department of Molecular Biology, Massachusetts General Hospital, Boston, MA 02114, USA.
D Department of Medicine, Infectious Diseases Division, Rhode Island Hospital, Warren Alpert Medical School of Brown University, Providence, RI 02903, USA.
E Department of Genetics, Harvard Medical School, Boston, MA 02115, USA.
F These authors contributed equally to this work.
G Corresponding author. Email: mkelso@uow.edu.au
Australian Journal of Chemistry 67(10) 1471-1480 https://doi.org/10.1071/CH14426
Submitted: 30 June 2014 Accepted: 14 August 2014 Published: 22 September 2014
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.
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