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Antimicrob Agents Chemother. 2018 Sep 24;62(10). pii: e01326-18. doi: 10.1128/AAC.01326-18. Print 2018 Oct.

Genetic Determinants of Penicillin Tolerance in Vibrio cholerae.

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Department of Microbiology, Cornell University, Ithaca, New York, USA.
Weill Institute for Cell and Molecular Biology, Cornell University, Ithaca, New York, USA.
Howard Hughes Medical Institute and Brigham and Women's Hospital/Harvard Medical School, Boston, Massachusetts, USA.
Department of Molecular and Cellular Biochemistry and Department of Biology, Indiana University, Bloomington, Indiana, USA.
Department of Microbiology, Cornell University, Ithaca, New York, USA
Contributed equally


Many bacteria are resistant to killing (tolerant) by typically bactericidal antibiotics due to their ability to counteract drug-induced cell damage. Vibrio cholerae, the cholera agent, displays an unusually high tolerance to diverse inhibitors of cell wall synthesis. Exposure to these agents, which in other bacteria leads to lysis and death, results in a breakdown of the cell wall and subsequent sphere formation in V. cholerae Spheres readily recover to rod-shaped cells upon antibiotic removal, but the mechanisms mediating the recovery process are not well characterized. Here, we found that the mechanisms of recovery are dependent on environmental conditions. Interestingly, on agarose pads, spheres undergo characteristic stages during the restoration of rod shape. Drug inhibition and microscopy experiments suggest that class A penicillin binding proteins (aPBPs) play a more active role than the Rod system, especially early in sphere recovery. Transposon insertion sequencing (TnSeq) analyses revealed that lipopolysaccharide (LPS) and cell wall biogenesis genes, as well as the sigma E cell envelope stress response, were particularly critical for recovery. LPS core and O-antigen appear to be more critical for sphere formation/integrity and viability than lipid A modifications. Overall, our findings demonstrate that the outer membrane is a key contributor to beta lactam tolerance and suggest a role for aPBPs in cell wall biogenesis in the absence of rod-shape cues. Factors required for postantibiotic recovery could serve as targets for antibiotic adjuvants that enhance the efficacy of antibiotics that inhibit cell wall biogenesis.


antibiotic tolerance; beta-lactam; cell wall synthesis; outer membrane; penicillin-binding proteins; peptidoglycan

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