O'Donnell, J. Nicholas Theses Advised
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Item Alternative Treatment Options against Carbapenem-Resistant Acinetobacter baumannii Infections(Albany College of Pharmacy and Health Sciences Theses, 2022-08) Putra, Vibert '22Carbapenem-resistant Acinetobacter baumanii (CRAB) is a multidrug-resistant nosocomial gram-negative pathogen that has become increasingly prevalent in the United States. CRAB has been labelled by the U.S. Centre for Disease Control and World Health Organisation as an “urgent threat” and “critical priority”, respectively. Due to its plethora of resistance arsenals, current treatment options against CRAB are extremely limited and combination treatments have become the norm. The purpose of this study to explore alternative combination treatments by evaluating clinically used antibiotic combinations and identifying a novel non-antibiotic combination strategy. Polymyxin B plus meropenem and polymyxin B plus minocycline were evaluated by in vitro hollow fibre infection models against minocycline-susceptible clinical CRAB strains. Our results showed polymyxin B combination with meropenem have greater bacterial killing despite minocycline monotherapy susceptibility in vitro. Previous studies showed that a USFDA-approved rheumatoid arthritis drug, auranofin, inhibits bacterial thioredoxin reductase within the antioxidant system that restores protein structures damaged by oxidative stress and regulates downstream effector proteins. Thioredoxin reductase activates thioredoxin A (TrxA), which is the effector protein in the thioredoxin system. Our 24-hour static concentration time kill assays showed that auranofin and meropenem combinations were beneficial against clinical CRAB isolates but not meropenem-susceptible clinical isolate. Furthermore, disc diffusion assay showed that auranofin has additive effects with minocycline, colistin, and chloramphenicol. Our total antioxidant assay showed that the TrxA-deleted mutant showed has significantly increased total antioxidant activity under meropenem stress, suggesting that the pathogen can compensate for the lack of antioxidant activity from the thioredoxin system. Hence, we propose that the increased antibiotic susceptibility observed under auranofin treatment was due to thioredoxin modulation of resistance mechanisms. Our study showed that TrxA modulates tetracycline efflux pump activities, while TrxA only modulates baseline total β-lactamase activities and not its induction overtime under meropenem stress. Therefore, our study showed the two potential avenues of therapies against CRAB infections that can either be applied immediately in the clinics or further characterised in vitro. Further evaluation of polymyxin B plus meropenem combination dose ranges and determination of thioredoxin role in modulation of resistance are needed to develop optimal treatments.