scholarly journals Ciprofloxacin-Resistant Salmonella enterica Serovar Typhimurium Strains Are Difficult To Select in the Absence of AcrB and TolC

2006 ◽  
Vol 50 (1) ◽  
pp. 38-42 ◽  
Author(s):  
Vito Ricci ◽  
Peter Tzakas ◽  
Anthony Buckley ◽  
Nick C. Coldham ◽  
Laura J. V. Piddock
Keyword(s):  
Salmonella Enterica ◽  
Salmonella Enterica Serovar Typhimurium ◽  
Efflux Pump ◽  
Multiple Antibiotic Resistance ◽  
Efflux System ◽  
Efflux Pump Inhibitor ◽  
Serovar Typhimurium ◽  
Resistant Mutants ◽  
Selection Of ◽  
Selection Of Resistance

ABSTRACT It has been proposed that lack of a functional efflux system(s) will lead to a lower frequency of selection of resistance to fluoroquinolones and other antibiotics. We constructed five strains of Salmonella enterica serovar Typhimurium SL1344 that lacked efflux gene components of resistance nodulation cell division pumps (acrB, acrD, acrF, acrBacrF, and tolC) plus three strains that lack genes that effect efflux gene expression (marA, soxS, and ramA) and a hypermutable strain (mutS::aph). Strains were exposed to ciprofloxacin at 2× the MIC in agar, in the presence and absence of Phe-Arg-β-naphthylamide, an efflux pump inhibitor. Mutants were selected from all strains except those lacking acrB, tolC, or acrBacrF. For strains from which mutants were selected, there were no significant differences between the frequencies of resistance. Except for mutants of the ramA::aph strain, two phenotypes arose: resistance to quinolones only and multiple antibiotic resistance (MAR). ramA::aph mutants were resistant to quinolones only, suggesting a role for ramA in MAR in S. enterica serovar Typhimurium. Phe-Arg-β-naphthylamide (20 μg/ml) had no effect on the frequencies of resistance or ciprofloxacin MICs. In conclusion, functional AcrB and TolC in S. enterica serovar Typhimurium are important for the selection of ciprofloxacin-resistant mutants.

scholarly journals Evidence for an Efflux Pump Mediating Multiple Antibiotic Resistance in Salmonella enterica Serovar Typhimurium

2000 ◽  
Vol 44 (11) ◽  
pp. 3118-3121 ◽  
Author(s):  
Laura J. V. Piddock ◽  
David G. White ◽  
Karl Gensberg ◽  
Lilian Pumbwe ◽  
Deborah J. Griggs
Keyword(s):  
Antibiotic Resistance ◽  
Salmonella Enterica ◽  
Salmonella Enterica Serovar Typhimurium ◽  
Efflux Pump ◽  
Northern Blotting ◽  
Multiple Antibiotic Resistance ◽  
Reverse Transcription Pcr ◽  
Carbonyl Cyanide ◽  
Serovar Typhimurium

ABSTRACT The mechanism of multiple antibiotic resistance in six isolates ofSalmonella enterica serovar Typhimurium recovered from a patient treated with ciprofloxacin was studied to investigate the role of efflux in the resistance phenotype. Compared to the patient's pretherapy isolate (L3), five of six isolates accumulated less ciprofloxacin, three of six isolates accumulated less chloramphenicol, and all six accumulated less tetracycline. The accumulation of one or more antibiotics was increased by carbonyl cyanidem-chlorophenylhydrazone to concentrations similar to those accumulated by L3 for all isolates except one, in which accumulation of all three agents remained approximately half that of L3. All isolates had the published wild-type sequences of marO andmarR. No increased expression of marA,tolC, or soxS was observed by Northern blotting; however, three isolates showed increased expression ofacrB, which was confirmed by quantitative competitive reverse transcription-PCR. However, there were no mutations withinacrR or the promoter region of acrAB in any of the isolates.

scholarly journals The AcrAB-TolC efflux system of Salmonella enterica serovar Typhimurium plays a role in pathogenesis

2006 ◽  
Vol 8 (5) ◽  
pp. 847-856 ◽  
Author(s):  
Anthony M. Buckley ◽  
Mark A. Webber ◽  
Sue Cooles ◽  
Luke P. Randall ◽  
Roberto M. La Ragione ◽  
...  
Keyword(s):  
Salmonella Enterica ◽  
Salmonella Enterica Serovar Typhimurium ◽  
Efflux System ◽  
Serovar Typhimurium

scholarly journals Contribution of Target Gene Mutations and Efflux to Decreased Susceptibility of Salmonella enterica Serovar Typhimurium to Fluoroquinolones and Other Antimicrobials

2006 ◽  
Vol 51 (2) ◽  
pp. 535-542 ◽  
Author(s):  
Sheng Chen ◽  
Shenghui Cui ◽  
Patrick F. McDermott ◽  
Shaohua Zhao ◽  
David G. White ◽  
...  
Keyword(s):  
Salmonella Enterica ◽  
Efflux Pump ◽  
Critical Role ◽  
Gene Mutations ◽  
Efflux Pumps ◽  
Fluoroquinolone Resistance ◽  
Naturally Occurring ◽  
Serovar Typhimurium ◽  
Resistant Mutants ◽  
Increased Susceptibility

ABSTRACT 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 μg/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 β-lactams. The expression of efflux pump genes acrA, acrB, acrE, acrF, emrB, emrD, and mdlB were substantially increased (≥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 ≥32 μg/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.

scholarly journals Membrane Topology of the ZntB Efflux System of Salmonella enterica Serovar Typhimurium

2003 ◽  
Vol 185 (1) ◽  
pp. 374-376 ◽  
Author(s):  
Andreia M. Caldwell ◽  
Ronald L. Smith
Keyword(s):  
Salmonella Enterica ◽  
Salmonella Enterica Serovar Typhimurium ◽  
Integral Membrane Protein ◽  
Membrane Topology ◽  
Membrane Domain ◽  
Efflux System ◽  
Hybrid Proteins ◽  
Serovar Typhimurium ◽  
Membrane Spanning ◽  
Derivatives Of

ABSTRACT The membrane topology of the ZntB Zn2+ transport protein of Salmonella enterica serovar Typhimurium was determined by constructing deletion derivatives of the protein and genetically fusing them to blaM or lacZ cassettes. The enzymatic activities of the hybrid proteins indicate that ZntB is a bitopic integral membrane protein consisting largely of two independent domains. The first 266 amino acids form a large, highly charged domain within the cytoplasm, while the remaining 61 residues form a small membrane domain containing two membrane-spanning segments. The overall orientation towards the cytoplasm is consistent with the ability of ZntB to facilitate zinc efflux.

scholarly journals Using In Vitro Dynamic Models To Evaluate Fluoroquinolone Activity against Emergence of Resistant Salmonella enterica Serovar Typhimurium

2016 ◽  
Vol 61 (2) ◽  
Author(s):  
Seung-Jin Lee ◽  
Elias Gebru Awji ◽  
Na-hye Park ◽  
Seung-Chun Park
Keyword(s):  
Salmonella Enterica ◽  
Dynamic Models ◽  
Resistant Bacteria ◽  
Antibacterial Drug ◽  
Bacterial Killing ◽  
Mutant Prevention Concentration ◽  
Serovar Typhimurium ◽  
Resistant Mutants ◽  
Selection Of

ABSTRACT The objectives of this study were to determine pharmacokinetic/pharmacodynamic (PK/PD) indices of fluoroquinolones that minimize the emergence of resistant Salmonella enterica serovar Typhimurium (S. Typhimurium) using in vitro dynamic models and to establish mechanisms of resistance. Three fluoroquinolones, difloxacin (DIF), enrofloxacin (ENR), and marbofloxacin (MAR), at five dose levels and 3 days of treatment were simulated. Bacterial killing-regrowth kinetics and emergence of resistant bacteria after antibacterial drug exposure were quantified. PK/PD indices associated with different levels of antibacterial activity were computed. Mechanisms of fluoroquinolone resistance were determined by analyzing target mutations in the quinolone resistance-determining regions (QRDRs) and by analyzing overexpression of efflux pumps. Maximum losses in susceptibility of fluoroquinolone-exposed S. Typhimurium occurred at a simulated AUC/MIC ratio (area under the concentration-time curve over 24 h in the steady state divided by the MIC) of 47 to 71. Target mutations in gyrA (S83F) and overexpression of acrAB-tolC contributed to decreased susceptibility in fluoroquinolone-exposed S. Typhimurium. The current data suggest AUC/MIC (AUC/mutant prevention concentration [MPC])-dependent selection of resistant mutants of S. Typhimurium, with AUC/MPC ratios of 69 (DIF), 62 (ENR), and 39 (MAR) being protective against selection of resistant mutants. These values could not be achieved in veterinary clinical areas under the current recommended therapeutic doses of the fluoroquinolones, suggesting the need to reassess the current dosing regimen to include both clinical efficacy and minimization of emergence of resistant bacteria.

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