Contribution of target gene mutations and efflux to decreased susceptibility of Salmonella enterica serovar typhimurium to fluoroquinolones and other antimicrobials.
The mechanisms involved in fluoroquinolone resistance in Salmonella enterica include target alterations and overexpression of efflux pumps. The present study evaluated the role of known and putative multidrug resistance efflux pumps and mutations in topoisomerase genes among laboratory-selected and naturally occurring fluoroquinolone-resistant Salmonella enterica serovar Typhimurium strains. Strains with ciprofloxacin MICs of 0.25, 4, 32, and 256 microg/ml were derived in vitro using serovar Typhimurium S21. These mutants also showed decreased susceptibility or resistance to many nonfluoroquinolone antimicrobials, including tetracycline, chloramphenicol, and several beta-lactams. The expression of efflux pump genes acrA, acrB, acrE, acrF, emrB, emrD, and mdlB were substantially increased (>or=2-fold) among the fluoroquinolone-resistant mutants. Increased expression was also observed, but to a lesser extent, with three other putative efflux pumps: mdtB (yegN), mdtC (yegO), and emrA among mutants with ciprofloxacin MICs of >or=32 microg/ml. Deletion of acrAB or tolC in S21 and its fluoroquinolone-resistant mutants resulted in increased susceptibility to fluoroquinolones and other tested antimicrobials. In naturally occurring fluoroquinolone-resistant serovar Typhimurium strains, deletion of acrAB or tolC increased fluoroquinolone susceptibility 4-fold, whereas replacement of gyrA double mutations (S83F D87N) with wild-type gyrA increased susceptibility>500-fold. These results indicate that a combination of topoisomerase gene mutations, as well as enhanced antimicrobial efflux, plays a critical role in the development of fluoroquinolone resistance in both laboratory-derived and naturally occurring quinolone-resistant serovar Typhimurium strains.
Chen
Sheng
S
Department of Nutrition and Food Science, 0112 Skinner Building, University of Maryland, College Park, MD 20742, USA.
Cui
Shenghui
S
McDermott
Patrick F
PF
Zhao
Shaohua
S
White
David G
DG
Paulsen
Ian
I
Meng
Jianghong
J
D000818:Animals; D000890:Anti-Infective Agents / Q000494:pharmacology*; D026942:DNA Topoisomerases / Q000235:genetics; D024881:Drug Resistance, Bacterial / Q000235:genetics; D024841:Fluoroquinolones / Q000494:pharmacology*; D018390:Gene Targeting; D005798:Genes, Bacterial; D009154:Mutation; D012481:Salmonella Infections, Animal / Q000188:drug therapy / Q000382:microbiology; D012486:Salmonella typhimurium / Q000187:drug effects / Q000235:genetics
D000890:Anti-Infective Agents; D024841:Fluoroquinolones; D026942:DNA Topoisomerases