Bactericidal effect of colistin on planktonic Pseudomonas aeruginosa is independent of hydroxyl radical formation

Brochmann, Rikke Prejh; Toft, Anders; Ciofu, Oana; Briales, Alejandra; Kolpen, Mette; Hempel, Casper; Bjarnsholt, Thomas; Høiby, Niels; Jensen, Peter Østrup

doi:10.1016/j.ijantimicag.2013.10.015

Cited by 57 publications

(67 citation statements)

References 34 publications

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“…NADH-quinone oxidoreductase)6465. However, the association of free radicals in the mechanism of antibiotic bacterial killing is disputable6667686970. In our analysis the reduced form of glutathione (GSH), an important indicator of oxidative stress, was not detected, as it was likely oxidized to glutathione disulfide (GSSG) during sample preparation and/or storage71.…”

Section: Discussionmentioning

confidence: 78%

Untargeted metabolomics analysis reveals key pathways responsible for the synergistic killing of colistin and doripenem combination against Acinetobacter baumannii

Maifiah

Creek

Nation

et al. 2017

Sci Rep

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Combination therapy is deployed for the treatment of multidrug-resistant Acinetobacter baumannii, as it can rapidly develop resistance to current antibiotics. This is the first study to investigate the synergistic effect of colistin/doripenem combination on the metabolome of A. baumannii. The metabolite levels were measured using LC-MS following treatment with colistin (2 mg/L) or doripenem (25 mg/L) alone, and their combination at 15 min, 1 hr and 4 hr (n = 4). Colistin caused early (15 min and 1 hr) disruption of the bacterial outer membrane and cell wall, as demonstrated by perturbation of glycerophospholipids and fatty acids. Concentrations of peptidoglycan biosynthesis metabolites decreased at 4 hr by doripenem alone, reflecting its mechanism of action. The combination induced significant changes to more key metabolic pathways relative to either monotherapy. Down-regulation of cell wall biosynthesis (via D-sedoheptulose 7-phosphate) and nucleotide metabolism (via D-ribose 5-phosphate) was associated with perturbations in the pentose phosphate pathway induced initially by colistin (15 min and 1 hr) and later by doripenem (4 hr). We discovered that the combination synergistically killed A. baumannii via time-dependent inhibition of different key metabolic pathways. Our study highlights the significant potential of systems pharmacology in elucidating the mechanism of synergy and optimizing antibiotic pharmacokinetics/pharmacodynamics.

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Section: Discussionmentioning

confidence: 78%

Untargeted metabolomics analysis reveals key pathways responsible for the synergistic killing of colistin and doripenem combination against Acinetobacter baumannii

Maifiah

Creek

Nation

et al. 2017

Sci Rep

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“…We have shown increased production of reactive oxygen species in bacterial cells exposed to sub-MIC ciprofloxacin (Jørgensen et al, 2013) and that a catalase mutant survived poorly in the presence of ciprofloxacin compared to the wild-type (Brochmann et al, 2014). Our data suggest that the decreased protease activity in the ciprofloxacin-evolved population cannot be explained by QS-dependent regulation.…”

mentioning

confidence: 63%

“…Although we do not have an explanation for this metabolic shift during evolution at subinhibitory levels of ciprofloxacin, we might speculate that upregulation of denitrification probably occurs to compensate for the metabolic burden of acquired mutations causing ciprofloxacin resistance. Alternatively, the shift from aerobic to anaerobic metabolism might be a metabolic adaptation to reduce the formation of reactive oxygen species and thus the oxidative stress burden during continuous exposure to ciprofloxacin (Brochmann et al, 2014;Dwyer et al, 2009). Different morphotypes were observed even in the ancestor populations of both PAO1 and DmutS.…”

Section: Discussionmentioning

confidence: 99%

The phenotypic evolution of Pseudomonas aeruginosa populations changes in the presence of subinhibitory concentrations of ciprofloxacin

et al. 2016

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Ciprofloxacin is a widely used antibiotic, in the class of quinolones, for treatment of Pseudomonas aeruginosa infections. The immediate response of P. aeruginosa to subinhibitory concentrations of ciprofloxacin has been investigated previously. However, the long-term phenotypic adaptation, which identifies the fitted phenotypes that have been selected during evolution with subinhibitory concentrations of ciprofloxacin, has not been studied. We chose an experimental evolution approach to investigate how exposure to subinhibitory concentrations of ciprofloxacin changes the evolution of P. aeruginosa populations compared to unexposed populations. Three replicate populations of P. aeruginosa PAO1 and its hypermutable mutant DmutS were cultured aerobically for approximately 940 generations by daily passages in LB medium with and without subinhibitory concentration of ciprofloxacin and aliquots of the bacterial populations were regularly sampled and kept at 280 8C for further investigations. We investigate here phenotypic changes between the ancestor (50 colonies) and evolved populations (120 colonies/strain). Decreased protease activity and swimming motility, higher levels of quorum-sensing signal molecules and occurrence of mutator subpopulations were observed in the ciprofloxacin-exposed populations compared to the ancestor and control populations. Transcriptomic analysis showed downregulation of the type III secretion system in evolved populations compared to the ancestor population and upregulation of denitrification genes in ciprofloxacin-evolved populations. In conclusion, the presence of antibiotics at subinhibitory concentration in the environment affects bacterial evolution and further studies are needed to obtain insight into the dynamics of the phenotypes and the mechanisms involved.

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“…In addition to being dependent on the activity of the TCA cycle generation of lethal amounts of OH · is reliant on the available electron acceptors as both the bactericidal activity and the [109]. Thus, the lethal effect mediated by formation of OH during bactericidal treatment with antibiotics depends on aerobic respiration and metabolic activity in order to develop the required reactive oxygen species (ROS).…”

Section: Hydroxyl Radical Formation During Antibiotic Treatment Of Bimentioning

confidence: 99%

“…Colistin has been shown to be such an antibiotic [109]. Combination therapy with colistin and tobramycin was shown to efficiently eliminate the bacteria in in vitro P. aeruginosa biofilms [74].…”

Section: Accepted Manuscriptmentioning

confidence: 99%

Antimicrobial resistance, respiratory tract infections and role of biofilms in lung infections in cystic fibrosis patients

Ciofu

Tolker‐Nielsen

Jensen

et al. 2015

Advanced Drug Delivery Reviews

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Bactericidal effect of colistin on planktonic Pseudomonas aeruginosa is independent of hydroxyl radical formation

Cited by 57 publications

References 34 publications

Untargeted metabolomics analysis reveals key pathways responsible for the synergistic killing of colistin and doripenem combination against Acinetobacter baumannii

Untargeted metabolomics analysis reveals key pathways responsible for the synergistic killing of colistin and doripenem combination against Acinetobacter baumannii

The phenotypic evolution of Pseudomonas aeruginosa populations changes in the presence of subinhibitory concentrations of ciprofloxacin

Antimicrobial resistance, respiratory tract infections and role of biofilms in lung infections in cystic fibrosis patients

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