Abstract
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 than 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 Escherichia coli and Klebsiella pneumoniae. In this study, we demonstrate that zinc blocks the SOS-induced development of chloramphenicol resistance in Enterobacter cloacae. Zinc also blocked the transfer of an extended spectrum beta-lactamase (ESBL) 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 E. cloacae. Other divalent metals, such as iron and manganese, failed to inhibit these responses. Electrophoretic mobility shift assays (EMSAs) 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. This suggests a mechanism for zinc's inhibitory effects on bacterial SOS responses, including hypermutation.
Highlights
The term “SOS response” as descriptor of a bacterial reactions to DNA damage was coined about 1975, the same year that the ship Edmund Fitzgerald sank in Lake Superior without sending out an SOS distress call
In contrast to the study by Beaber et al, who worked with V. cholerae, an organism that is naturally competent for uptake of extracellular DNA, E. coli and related enterics are not naturally competent, and they can take up DNA from the environment, such DNA is often degraded and used as food rather than incorporated into their genomes (Finkel and Kolter, 2001; Chen and Dubnau, 2004; Palchevskiy and Finkel, 2006)
The SOS response has been discussed in the molecular biology literature for over 40 years (Radman, 1975), appreciation of the role of the SOS pathway in generation of antibiotic resistance has been very slow to percolate into the fields of clinical microbiology and infectious diseases
Summary
The term “SOS response” as descriptor of a bacterial reactions to DNA damage was coined about 1975, the same year that the ship Edmund Fitzgerald sank in Lake Superior without sending out an SOS distress call. The SOS response triggers a constellation of changes in the bacterial cell, including cellular elongation, suspension of cell division, induction of DNA repair pathways, induction of latent bacteriophages, expression of bacteriophage-encoded toxins, and increased expression of error-prone DNA polymerases (Goodman, 2002). The latter underlies the increased mutation rate observed when the SOS response is strongly induced. Their work and that of others have led to increased interest in whether SOS inhibitors could block emergence of antibiotic resistance (Nautiyal et al, 2014; Alam et al, 2016).
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