Efflux pumps and inhibitors of serum grown Acinetobacter baumannii
Acinetobacter baumannii has been designated as one of the six ESKAPE (Enterococcus, Staphylococcus, Klebsiella, Acinetobacter, Pseudomonas and Enterobacter) bacterial pathogens of greatest healthcare concern. While the organism is capable of producing an array of bacterial infections, A. baumannii bacteremia is a primary concern, resulting in mortality rates as high as 80% in certain patient populations. We have previously shown that the organism upregulates a repertoire of drug efflux pumps and displays corresponding antibiotic tolerance during growth in human serum, suggesting that this phenomenon may account for the observed clinical failure of antibiotics against otherwise susceptible strains. Consistent with that prediction, we showed that serum-mediated tolerance to minocycline and ciprofloxacin is negated by the addition of known efflux pump inhibitors (EPI). From these perspectives, adjunctive EPI + antibiotics therapeutic strategies may prove to be a promising approach for treating A. baumannii bacteremia. At issue, currently available EPIs are not clinically relevant. Our research focuses on two specific areas: developing novel EPI chemical scaffolds to be used in adjunctive therapy with antibiotics and defining the molecular machinery that governs A. baumannii’s antibiotic tolerance during growth in human serum. Toward those goals we have: A. identified and characterized two novel EPI backbones that potentiate the activity of antibiotics against A. baumannii in a serum-specific manner and B. identified fourteen transposon mutants that exhibit a decrease in serum-specific efflux of antibiotics.
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