Inhibitors of Multidrug Efflux Pumps as Resistance Blocking Agents

Fluoroquinolones (FQs) are among the limited arsenal of antibiotics available to treat highly intrinsic-resistant Gram-negative bacteria, such as Acinetobacter and Pseudomonas, which are considered to be among the most difficult hospital-acquired infections to treat and control. Over the last decade antibiotic efflux due to the activity of multi-drug resistance pumps (MDR) emerged as one of the major contributing factors to both acquired and intrinsic resistance to FQs in these and other Gram-negative bacteria. The major objective of this proposal is to discover lead molecule inhibitors of bacterial multi-drug resistance pumps that can be combined with FQ antibiotics to restore their effectiveness and significantly reduce further resistance development. We will specifically target Acinetobacter baumannii, the common agent of wound infections and an important nosocomial pathogen. Previous screening of our 240K compound library and subsequent analog searches identified a sub-set of ~2000 compounds containing structurally diverse families of efflux pumps inhibitors (EPIs) from P. aeruginosa, E. coli, and H. influenzae. Broad-spectrum EPIs, capable of inhibiting single and multiple efflux pumps have been identified. We will use these compounds to search for EPIs against Acinetobacter pumps; this should significantly expedite selection of leads and successive development of novel resistance blocking agents.