The Complete and SOS-Mediated Response of Staphylococcus aureus to the Antibiotic Ciprofloxacin

Department of Chemistry, The Scripps Research Institute, La Jolla, CA 92037. Pathogen Functional Genomics Resource Center (PFGRC), The Institute for Genomic Research, Rockville, MD 20850

^* To whom correspondence should be addressed. Email: floyd{at}scripps.edu.

	Abstract

Staphylococcus aureus infections can be difficult to treat due to both multi-drug resistance and the organism's remarkable ability to persist in the host. Persistence and the evolution of resistance may be related to several complex regulatory networks, such as the SOS response, which modifies transcription in response to environmental stress. To understand how S. aureus persists during antibiotic therapy, and eventually emerges resistant, we characterized its global transcriptional response to ciprofloxacin. We find that ciprofloxacin induces prophage mobilization, as well as significant alterations in metabolism, most notably the up-regulation of the tricarboxylic acid cycle. In addition, we find that ciprofloxacin induces the SOS response, which, by comparison of a wild-type and a SOS-uninducible lexA mutant strain, we show includes the de-repression of sixteen genes. While the SOS response of S. aureus is much more limited than E. coli and B. subtilis, it is similar to P. aeruginosa and includes RecA, LexA, several hypothetical proteins, and a likely error-prone Y-family polymerase whose homologs in other bacteria are required for induced mutation. We also examined induced mutation and find that either the inability to de-repress the SOS response, or the lack of the LexA-regulated polymerase, renders S. aureus unable to evolve antibiotic resistance in vitro in response to UV damage. The data suggest that upregulation of the tricarboxylic acid cycle and induced mutation facilitate S. aureus persistence and evolution of resistance during antibiotic therapy.