The TCA cycle is not required for selection or survival of multidrug-resistant Salmonella.
Vito Ricci, Nicholas Loman, Mark Pallen, A Ivens, M Fookes, GC Langridge, J Wain, Laura Piddock
OBJECTIVES: The initial aim of this study was to use a systems biology approach to analyse a ciprofloxacin-selected multidrug-resistant (MDR) Salmonella enterica serotype Typhimurium, L664. METHODS: The whole genome sequence and transcriptome of L664 were analysed. Site-directed mutagenesis to recreate each mutation was carried out, followed by phenotypic characterization and mutation frequency analysis. As a mutation in the TCA cycle was detected we tested the controversial hypothesis regarding the bacterial response to bactericidal antibiotics, put forward by Kohanski et al. (Cell 2007; 130: 797-810 and Mol Cell 2010; 37: 311-20), that exposure of bacteria to agents such as ciprofloxacin produces reactive oxygen species (ROS), which transiently increase the mutation rate giving rise to MDR bacteria. RESULTS: L664 contained a mutation in ramR that conferred MDR. A mutation in tctA affected the TCA cycle and conferred the inability to grow on minimal agar. The virulence of L664 was not attenuated. Ciprofloxacin exposure produced ROS in L664 and SL1344 (tctA::aph), but it was reduced and occurred later. There were no significant differences in the rates of killing or mutations per generation to antibiotic resistance between the strains. CONCLUSIONS: Whilst we confirm production of ROS in response to ciprofloxacin, we have no data to support the hypothesis that this leads to selection of MDR strains. Our results indicate that the mutations in tctA and glgA were random as they did not pre-exist in the parental strain, and that the mutation in tctA did not provide a survival advantage or disadvantage in the presence of antibiotic.
Journal of Antimicrobial Chemotherapy
https://doi.org/10.1093/jac/dkr515
10.1093/jac/dkr515
Dive into the research topics of 'The TCA cycle is not required for selection or survival of multidrug-resistant Salmonella.'. Together they form a unique fingerprint.
Salmonella Medicine & Life Sciences 100%
Ciprofloxacin Medicine & Life Sciences 56%
Reactive Oxygen Species Medicine & Life Sciences 32%
Mutation Rate Medicine & Life Sciences 28%
Salmonella enterica Medicine & Life Sciences 16%
Unravelling the Network of Regulation of Multidrug Resistance in Salmonella Enterica
Piddock, L. & Busby, S.
Project: Research Councils
Multiple Drug Resistance 100%
Anti-Bacterial Agents 74%
Salmonella enterica 60%
Microbial Drug Resistance 56%
Gram-Negative Bacteria 46%
Unravelling Multiple Antibiotic Resistance in Salmonella Enterica
Piddock, L.
Ricci, V., Loman, N., Pallen, M., Ivens, A., Fookes, M., Langridge, GC., Wain, J., & Piddock, L. (2011). The TCA cycle is not required for selection or survival of multidrug-resistant Salmonella. Journal of Antimicrobial Chemotherapy. https://doi.org/10.1093/jac/dkr515
Ricci, Vito ; Loman, Nicholas ; Pallen, Mark ; Ivens, A ; Fookes, M ; Langridge, GC ; Wain, J ; Piddock, Laura. / The TCA cycle is not required for selection or survival of multidrug-resistant Salmonella. In: Journal of Antimicrobial Chemotherapy. 2011.
@article{b0af9c142e2549eaa8220962438d7754,
title = "The TCA cycle is not required for selection or survival of multidrug-resistant Salmonella.",
abstract = "OBJECTIVES: The initial aim of this study was to use a systems biology approach to analyse a ciprofloxacin-selected multidrug-resistant (MDR) Salmonella enterica serotype Typhimurium, L664. METHODS: The whole genome sequence and transcriptome of L664 were analysed. Site-directed mutagenesis to recreate each mutation was carried out, followed by phenotypic characterization and mutation frequency analysis. As a mutation in the TCA cycle was detected we tested the controversial hypothesis regarding the bacterial response to bactericidal antibiotics, put forward by Kohanski et al. (Cell 2007; 130: 797-810 and Mol Cell 2010; 37: 311-20), that exposure of bacteria to agents such as ciprofloxacin produces reactive oxygen species (ROS), which transiently increase the mutation rate giving rise to MDR bacteria. RESULTS: L664 contained a mutation in ramR that conferred MDR. A mutation in tctA affected the TCA cycle and conferred the inability to grow on minimal agar. The virulence of L664 was not attenuated. Ciprofloxacin exposure produced ROS in L664 and SL1344 (tctA::aph), but it was reduced and occurred later. There were no significant differences in the rates of killing or mutations per generation to antibiotic resistance between the strains. CONCLUSIONS: Whilst we confirm production of ROS in response to ciprofloxacin, we have no data to support the hypothesis that this leads to selection of MDR strains. Our results indicate that the mutations in tctA and glgA were random as they did not pre-exist in the parental strain, and that the mutation in tctA did not provide a survival advantage or disadvantage in the presence of antibiotic.",
author = "Vito Ricci and Nicholas Loman and Mark Pallen and A Ivens and M Fookes and GC Langridge and J Wain and Laura Piddock",
doi = "10.1093/jac/dkr515",
journal = "Journal of Antimicrobial Chemotherapy",
Ricci, V, Loman, N, Pallen, M, Ivens, A, Fookes, M, Langridge, GC, Wain, J & Piddock, L 2011, 'The TCA cycle is not required for selection or survival of multidrug-resistant Salmonella.', Journal of Antimicrobial Chemotherapy. https://doi.org/10.1093/jac/dkr515
The TCA cycle is not required for selection or survival of multidrug-resistant Salmonella. / Ricci, Vito; Loman, Nicholas; Pallen, Mark; Ivens, A; Fookes, M; Langridge, GC; Wain, J; Piddock, Laura.
In: Journal of Antimicrobial Chemotherapy, 22.12.2011.
T1 - The TCA cycle is not required for selection or survival of multidrug-resistant Salmonella.
AU - Ricci, Vito
AU - Loman, Nicholas
AU - Pallen, Mark
AU - Ivens, A
AU - Fookes, M
AU - Langridge, GC
AU - Wain, J
AU - Piddock, Laura
N2 - OBJECTIVES: The initial aim of this study was to use a systems biology approach to analyse a ciprofloxacin-selected multidrug-resistant (MDR) Salmonella enterica serotype Typhimurium, L664. METHODS: The whole genome sequence and transcriptome of L664 were analysed. Site-directed mutagenesis to recreate each mutation was carried out, followed by phenotypic characterization and mutation frequency analysis. As a mutation in the TCA cycle was detected we tested the controversial hypothesis regarding the bacterial response to bactericidal antibiotics, put forward by Kohanski et al. (Cell 2007; 130: 797-810 and Mol Cell 2010; 37: 311-20), that exposure of bacteria to agents such as ciprofloxacin produces reactive oxygen species (ROS), which transiently increase the mutation rate giving rise to MDR bacteria. RESULTS: L664 contained a mutation in ramR that conferred MDR. A mutation in tctA affected the TCA cycle and conferred the inability to grow on minimal agar. The virulence of L664 was not attenuated. Ciprofloxacin exposure produced ROS in L664 and SL1344 (tctA::aph), but it was reduced and occurred later. There were no significant differences in the rates of killing or mutations per generation to antibiotic resistance between the strains. CONCLUSIONS: Whilst we confirm production of ROS in response to ciprofloxacin, we have no data to support the hypothesis that this leads to selection of MDR strains. Our results indicate that the mutations in tctA and glgA were random as they did not pre-exist in the parental strain, and that the mutation in tctA did not provide a survival advantage or disadvantage in the presence of antibiotic.
AB - OBJECTIVES: The initial aim of this study was to use a systems biology approach to analyse a ciprofloxacin-selected multidrug-resistant (MDR) Salmonella enterica serotype Typhimurium, L664. METHODS: The whole genome sequence and transcriptome of L664 were analysed. Site-directed mutagenesis to recreate each mutation was carried out, followed by phenotypic characterization and mutation frequency analysis. As a mutation in the TCA cycle was detected we tested the controversial hypothesis regarding the bacterial response to bactericidal antibiotics, put forward by Kohanski et al. (Cell 2007; 130: 797-810 and Mol Cell 2010; 37: 311-20), that exposure of bacteria to agents such as ciprofloxacin produces reactive oxygen species (ROS), which transiently increase the mutation rate giving rise to MDR bacteria. RESULTS: L664 contained a mutation in ramR that conferred MDR. A mutation in tctA affected the TCA cycle and conferred the inability to grow on minimal agar. The virulence of L664 was not attenuated. Ciprofloxacin exposure produced ROS in L664 and SL1344 (tctA::aph), but it was reduced and occurred later. There were no significant differences in the rates of killing or mutations per generation to antibiotic resistance between the strains. CONCLUSIONS: Whilst we confirm production of ROS in response to ciprofloxacin, we have no data to support the hypothesis that this leads to selection of MDR strains. Our results indicate that the mutations in tctA and glgA were random as they did not pre-exist in the parental strain, and that the mutation in tctA did not provide a survival advantage or disadvantage in the presence of antibiotic.
U2 - 10.1093/jac/dkr515
DO - 10.1093/jac/dkr515
JO - Journal of Antimicrobial Chemotherapy
JF - Journal of Antimicrobial Chemotherapy
Ricci V, Loman N, Pallen M, Ivens A, Fookes M, Langridge GC et al. The TCA cycle is not required for selection or survival of multidrug-resistant Salmonella. Journal of Antimicrobial Chemotherapy. 2011 Dec 22. https://doi.org/10.1093/jac/dkr515