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Front. Cell. Infect. Microbiol. | doi: 10.3389/fcimb.2018.00410

Zinc Blockade of SOS Response Inhibits Horizontal Transfer of Antibiotic Resistance Genes in Enteric Bacteria

 John K. Crane1, 2*, Muhammad B. Cheema3, 4, Michael A. Olyer1 and  MarkMark D. Sutton5
  • 1Division of Infectious Diseases ,Jacobs School of Medicine and Biomedical Sciences, University at Buffalo, United States
  • 2University at Buffalo, United States
  • 3Resident Physician, Catholic Health System, Buffalo, NY, United States
  • 4Jacobs School of Medicine and Biomedical Sciences, University at Buffalo, United States
  • 5Department of Biochemistry, Jacobs School of Medicine and Biomedical Sciences, University at Buffalo, United States

The SOS response is a conserved response to DNA damage that is found in Gram- negative and Gram-positive bacteria. When DNA damage is sustained and severe, activation of error-prone DNA polymerases can induce a higher mutation rate then is normally observed, which is called the SOS mutator phenotype or hypermutation. We previously showed that zinc blocked the hypermutation response induced by quinolone antibiotics and mitomycin C in E. coli and Klebsiella pneumoniae. In this study, we tested whether we could induce hypermutation in a different species of enteric bacteria, Enterobacter cloacae, and whether zinc would inhibit that hypermutation response.. We then tested whether we could exploit zinc’s activity as an SOS inhibitor to block the transfer of an antibiotic resistance gene, an extended spectrum beta-lactamase (ESBL), from Enterobacter to E. coli. Zinc blocked SOS-induced development of chloramphenicol resistance in E. cloacae, and also blocked transfer of an extended spectrum ß-lactamase gene from Enterobacter to a susceptible E. coli strain. A zinc ionophore, zinc pyrithione, was ~ 100-fold more potent than zinc salts in inhibition of ciprofloxacin-induced hypermutation in Enterobacter. Other divalent metals, such as iron and manganese, failed to inhibit these responses. Electrophorectic mobility shift assays (EMSA) revealed that zinc, but not iron or manganese, blocked the ability of the E. coli RecA protein to bind to single-stranded DNA, an important early step in the recognition of DNA damage in enteric bacteria.

Keywords: antibiotic resistance, recA, Electrophoretic mobility shift assay (EMSA), Enterobacter cloacae, Extended spectrum beta lactamase (ESBL), CTX-M27, Zinc pyrithione

Received: 01 Aug 2018; Accepted: 05 Nov 2018.

Edited by:

You-Hee Cho, CHA University, South Korea

Reviewed by:

Yang Zhang, University of Pennsylvania, United States
Chulhee Choi, Chungnam National University, South Korea  

Copyright: © 2018 Crane, Cheema, Olyer and Sutton. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

* Correspondence: Prof. John K. Crane, Division of Infectious Diseases ,Jacobs School of Medicine and Biomedical Sciences, University at Buffalo, Buffalo, United States, jcrane@buffalo.edu