Genetic Determinants of <i>Acinetobacter baumannii</i> Serum-Associated Adaptive Efflux-Mediated Antibiotic Resistance
<i>Acinetobacter baumannii</i> is a nosocomial pathogen of serious healthcare concern that is becoming increasingly difficult to treat due to antibiotic treatment failure. Recent studies have revealed that clinically defined antibiotic-susceptible strains upregulate the expression of a r...
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| Main Authors: | , , , , , , |
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| Format: | Book |
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MDPI AG,
2023-07-01T00:00:00Z.
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| Summary: | <i>Acinetobacter baumannii</i> is a nosocomial pathogen of serious healthcare concern that is becoming increasingly difficult to treat due to antibiotic treatment failure. Recent studies have revealed that clinically defined antibiotic-susceptible strains upregulate the expression of a repertoire of putative drug efflux pumps during their growth under biologically relevant conditions, e.g., in human serum, resulting in efflux-associated resistance to physiologically achievable antibiotic levels within a patient. This phenomenon, termed Adaptive Efflux Mediated Resistance (AEMR), has been hypothesized to account for one mechanism by which antibiotic-susceptible <i>A. baumannii</i> fails to respond to antibiotic treatment. In the current study, we sought to identify genetic determinants that contribute to <i>A. baumannii</i> serum-associated AEMR by screening a transposon mutant library for members that display a loss of the AEMR phenotype. Results revealed that mutation of a putative pirin-like protein, YhaK, results in a loss of AEMR, a phenotype that could be complemented by a wild-type copy of the <i>yhaK</i> gene and was verified in a second strain background. Ethidium bromide efflux assays confirmed that the loss of AEMR phenotype due to pirin-like protein mutation correlated with reduced overarching efflux capacity. Further, flow cytometry and confocal microscopy measures of a fluorophore 7-(dimethylamino)-coumarin-4-acetic acid (DMACA)-tagged levofloxacin isomer, ofloxacin, further verified that YhaK mutation reduces AEMR-mediated antibiotic efflux. RNA-sequencing studies revealed that YhaK may be required for the expression of multiple efflux-associated systems, including MATE and ABC families of efflux pumps. Collectively, the data indicate that the <i>A. baumannii</i> YhaK pirin-like protein plays a role in modulating the organism's adaptive efflux-mediated resistance phenotype. |
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| Item Description: | 10.3390/antibiotics12071173 2079-6382 |