Journal Article

Clinically Relevant Mutant DNA Gyrase Alters Supercoiling, Changes the Transcriptome, and Confers Multidrug Resistance

Webber, Mark A., Piddock, Laura J. V., Ivens, Alasdair, Whitehead, Rebekah, Fookes, Maria, Patel, Meha, Ricci, Vito

2013

Overview

Bacterial DNA is maintained in a supercoiled state controlled by the action of topoisomerases. Alterations in supercoiling affect fundamental cellular processes, including transcription. Here, we show that substitution at position 87 of GyrA of Salmonella influences sensitivity to antibiotics, including nonquinolone drugs, alters global supercoiling, and results in an altered transcriptome with increased expression of stress response pathways. Decreased susceptibility to multiple antibiotics seen with a GyrA Asp87Gly mutant was not a result of increased efflux activity or reduced reactive-oxygen production. These data show that a frequently observed and clinically relevant substitution within GyrA results in altered expression of numerous genes, including those important in bacterial survival of stress, suggesting that GyrA mutants may have a selective advantage under specific conditions. Our findings help contextualize the high rate of quinolone resistance in pathogenic strains of bacteria and may partly explain why such mutant strains are evolutionarily successful. IMPORTANCE Fluoroquinolones are a powerful group of antibiotics that target bacterial enzymes involved in helping bacteria maintain the conformation of their chromosome. Mutations in the target enzymes allow bacteria to become resistant to these antibiotics, and fluoroquinolone resistance is common. We show here that these mutations also provide protection against a broad range of other antimicrobials by triggering a defensive stress response in the cell. This work suggests that fluoroquinolone resistance mutations may be beneficial under a range of conditions. Fluoroquinolones are a powerful group of antibiotics that target bacterial enzymes involved in helping bacteria maintain the conformation of their chromosome. Mutations in the target enzymes allow bacteria to become resistant to these antibiotics, and fluoroquinolone resistance is common. We show here that these mutations also provide protection against a broad range of other antimicrobials by triggering a defensive stress response in the cell. This work suggests that fluoroquinolone resistance mutations may be beneficial under a range of conditions.

• Publisher: American Society for Microbiology,American Society of Microbiology
• Subject: Amino Acid Substitution / Anti-Bacterial Agents - metabolism / Antibiotics / Antimicrobial agents / Bacteria / Cell death / Cellular stress response / chromosomes / Conformation / Defensive behavior / DNA / DNA Gyrase - genetics / DNA Gyrase - metabolism / DNA topoisomerase / DNA topoisomerase (ATP-hydrolysing) / DNA, Superhelical - metabolism / Drug Resistance, Multiple, Bacterial / drugs / E coli / Enzymes / Fluoroquinolones / genes / Gram-negative bacteria / Humans / Microbial Sensitivity Tests / Multidrug resistance / multiple drug resistance / Mutagenesis / Mutant Proteins - genetics / Mutant Proteins - metabolism / Mutants / Mutation / Quinolones / Respiration / Salmonella / Salmonella typhimurium - drug effects / Salmonella typhimurium - enzymology / Salmonella typhimurium - genetics / Salmonella typhimurium - metabolism / Selection, Genetic / Strains (organisms) / Streptococcus infections / stress response / Stress, Physiological / Supercoiling / Transcriptome / Transcriptomes / virulent strains / Vitamin B