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Author Notes:

Philip N. Rather, prather@emory.edu

This work was supported by NIH R01 AI72219 to P.N.R. and R.A.B. In addition, P.N.R. is supported by grant R21 AI115183 and Department of Veterans Affairs awards I01 BX001725 and IK6BX004470. J.M.C. was supported by grant IK2BX005911 from the Department of Veterans Affairs. This study was also supported in part by funds and/or facilities provided by the Cleveland Department of Veterans Affairs, award number 1I01BX001974, to R.A.B. from the Biomedical Laboratory Research & Development Service of the VA Office of Research and Development and the Geriatric Research Education and Clinical Center VISN 10. A.J.C. is supported by a project grant (PJT 156353) from the Canadian Institutes of Health Research. A.C.A. holds a PGSD scholarship from the Natural Sciences and Engineering Research Council of Canada. The content is solely the responsibility of the authors and does not necessarily represent the official views of the NIH or the Department of Veterans Affairs.

Subjects:

Keywords:

  • Acinetobacter
  • antibiotic resistance
  • carbonic anhydrase
  • β-lactamase
  • Humans
  • Acinetobacter baumannii
  • Ethoxzolamide
  • Peptidoglycan
  • Acinetobacter Infections
  • beta-Lactamases
  • Anti-Bacterial Agents
  • Cell Physiological Phenomena
  • Microbial Sensitivity Tests

Collateral Changes in Cell Physiology Associated with ADC-7 b-Lactamase Expression in Acinetobacter baumannii

Tools:

Journal Title:

Microbiology Spectrum

Volume:

Volume 11, Number 3

Publisher:

, Pages e0464622-e0464622

Type of Work:

Article | Final Publisher PDF

Abstract:

The ADC (AmpC) b-lactamase is universally present in the Acinetobacter baumannii chromosome, suggesting it may have a yet-to-be-identified cellular function. Using peptidoglycan composition analysis, we show that overexpressing the ADC-7 b-lactamase in A. baumannii drives changes consistent with altered L,D-transpeptidase activity. Based on this, we tested whether cells overexpressing ADC-7 would exhibit new vulnerabilities. As proof of principle, a screen of transposon insertions revealed that an insertion in the distal 39 end of canB, encoding carbonic anhydrase, resulted in a significant loss of viability when the adc-7 gene was overexpressed. A canB deletion mutant exhibited a more pronounced loss of viability than the transposon insertion, and this became amplified when cells overexpressed ADC-7. Interestingly, overexpression of the OXA-23 or TEM-1 b-lactamases also led to a pronounced loss of viability in cells with reduced carbonic anhydrase activity. In addition, we demonstrate that reduced CanB activity led to increased sensitivity to peptidoglycan synthesis inhibitors and to the carbonic anhydrase inhibitor ethoxzolamide. Furthermore, this strain exhibited a synergistic interaction with the peptidoglycan inhibitor fosfomycin and ethoxzolamide. Our results highlight the impact of ADC-7 overexpression on cell physiology and reveal that the essential carbonic anhydrase CanB may represent a novel target for antimicrobial agents that would exhibit increased potency against b-lactamase-overexpressing A. baumannii. IMPORTANCE Acinetobacter baumannii has become resistant to all classes of antibiotics, with b-lactam resistance responsible for the majority of treatment failures. New classes of antimicrobials are needed to treat this high-priority pathogen. This study had uncovered a new genetic vulnerability in b-lactamase-expressing A. baumannii, where reduced carbonic anhydrase activity becomes lethal. Inhibitors of carbonic anhydrase could represent a new method for treating A. baumannii infections.
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