Novel and Promising Efflux Pump Inhibitors (EPI) to Control Bacterial Drug Resistance

The efflux pump (EP) is one of the major factors to develop antibiotic resistance in bacteria. There is not a single efflux pump inhibitor (EPI) which is in clinical practice. So, it is need of hour to discover new ideal EPI which can be used in combinations with FDA approved antibiotics.

The salient features of this technology are:

• Microbial fermentation derived previously uncharacterized efflux pump inhibitors (EPI's), having differential specificities towards Gram-positive (RP2) and Gram-negative (RP1) bacterial efflux pumps.
• RP1 & RP2 potentiates several antibiotics (4 to 64-folds), by inhibiting multiple efflux pumps in E. coli & S. aureus respectively. The potentiation activity was better than PAβN and Reserpine.
• The Antibiotic-EPI combination exhibited bactericidal effect in time-kill kinetics
• MPC (Mutation Prevention Concentration) of both the antibiotics was reduced, indicating their clinical significance in limiting the frequency of appearance of resistant mutants.
• Significantly extended post-antibiotic effects (PAEs) as compared to antibiotics tested alone.
• Both the EPIs appear to be safe on mammalian cellsand non-hemolytic in nature.
• Unlike CCCP, RP1 and RP2 neither dissipates proton gradient used by the pump nor abolishes the total ATP pool within bacterial cell.
• RP1 or RP2 did not seem to block mammalian cell Ca⁺² channels, unlike Verapamil
• The ability of RP1 and RP2 to reduce the intracellular invasion of E. coli and S. aureus respectively in J774 macrophage cell lines

• Significantly extended post-antibiotic effects (PAEs) as compared to antibiotics tested alone.
• Both the EPIs appear to be safe on mammalian cellsand non-hemolytic in nature.