Inhibitors of adaptive efflux mediated resistance in Acinetobacter baumannii

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PROJECT ABSTRACT Acinetobacter baumannii has emerged as a major healthcare concern due, in part, to the organism’s propensity to develop resistance to front-line antibiotics. The A. baumannii resistome includes aminoglycoside and β-lactam modifying factors, but is primarily comprised of at least 40 drug efflux systems belonging to 6 distinct pump families. Intrinsic multidrug resistance occurs via mutations that lead to overexpression of one or more efflux systems, thereby allowing the organism to extrude antibiotics from the cell. Recently we discovered efflux systems also modulate adaptive A. baumannii antibiotic resistance. Meaning, transfer of antibiotic susceptible strains to physiologically relevant growth conditions, such as human serum, leads to the upregulation of at least 18 annotated efflux pump components, which in turn allows for efflux mediated resistance to antibiotic levels that are achievable within a patient. This phenomenon, which has been termed adaptive efflux mediated resistance (AEMR) by Handcock and colleagues, has been hypothesized to be one means by which otherwise antibiotic susceptible strains fail to respond to antibiotic treatment within the clinic. We hypothesized that the hyper-efflux phenotype of AEMR conditions would provide a unique and innovative screening platform to identify broad- spectrum efflux pump inhibitors that inhibit multiple A. baumannii efflux pumps. Indeed, a pilot high throughput screen led to the identification of the benzenesulfonamide class of efflux pump inhibitors that eliminate AEMR and antibiotic resistance within strains that overexpress efflux pumps that are notorious causes of multidrug resistance among clinical isolates. Our goals herein are to 1. Expand our screening approach to include a larger, chemically diverse compound library to arrive at additional chemical series of A. baumannii efflux pump inhibitors (EPIs), 2. Use medicinal chemistry to optimize the benzenesulfonamide and as many as two additional chemical series of EPIs, 3. Define the cellular target of the benzenesulfonamides and new chemical classes of EPIs, and 4. Test the in vivo efficacy of front runner compounds against A. baumannii strains that exhibit efflux mediated multidrug resistance.