Complete and SOS-mediated response of Staphylococcus aureus to the antibiotic ciprofloxacin.
Staphylococcus aureus infections can be difficult to treat due to both multidrug 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 found 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 found that ciprofloxacin induces the SOS response, which we show, by comparison of a wild-type strain and a non-SOS-inducible lexA mutant strain, includes the derepression of 16 genes. While the SOS response of S. aureus is much more limited than those of Escherichia coli and Bacillus subtilis, it is similar to that of Pseudomonas 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 found that either the inability to derepress 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 up-regulation of the tricarboxylic acid cycle and induced mutation facilitate S. aureus persistence and evolution of resistance during antibiotic therapy.
Cirz
Ryan T
RT
Department of Chemistry, The Scripps Research Institute, La Jolla, CA 92037, USA.
Jones
Marcus B
MB
Gingles
Neill A
NA
Minogue
Timothy D
TD
Jarrahi
Behnam
B
Peterson
Scott N
SN
Romesberg
Floyd E
FE
D000900:Anti-Bacterial Agents / Q000494:pharmacology; D001426:Bacterial Proteins / Q000235:genetics / Q000378:metabolism; D002939:Ciprofloxacin / Q000494:pharmacology*; D002952:Citric Acid Cycle / Q000235:genetics / Q000502:physiology; D024881:Drug Resistance, Bacterial; D015964:Gene Expression Regulation, Bacterial; D009154:Mutation; D020411:Oligonucleotide Array Sequence Analysis / Q000379:methods; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013014:SOS Response, Genetics / Q000235:genetics / Q000502:physiology*; D013211:Staphylococcus aureus / Q000187:drug effects* / Q000378:metabolism / Q000528:radiation effects; D014466:Ultraviolet Rays
D000900:Anti-Bacterial Agents; D001426:Bacterial Proteins; D002939:Ciprofloxacin