Effect of mutator <i>P. aeruginosa</i> on antibiotic resistance acquisition and respiratory function in cystic fibrosis

Ferroni, Agnès; Guillemot, Didier; Moumile, Kaoutar; Bernède, Claire; Bourgeois, M. Le; Waernessyckle, Serge; Descamps, Philippe; Sermet‐Gaudelus, Isabelle; Lenoir, G.; Berche, Patrick; Taddéi, François

doi:10.1002/ppul.21076

Cited by 54 publications

(62 citation statements)

References 27 publications

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“…We provide evidence that accumulation of mutators in the CF lung is associated especially with multi-drug resistance development, thus suggesting that the intensive antibiotic treatment is one of the main selective pressures for the maintenance and amplification of mutators, a hypothesis that is supported by several publications (Oliver et al, 2000;Ciofu et al, 2005;Ferroni et al, 2009). …”

Section: Discussionsupporting

confidence: 57%

“…It has been shown that the prevalence of P. aeruginosa mutators increases with time during chronic lung infection due to positive selection of the mutators in the CF lung (Ciofu et al, 2005;Hogardt et al, 2007;Mena et al, 2008) Association between strong mutators and development of resistance to antibiotics has been reported on several occasions (Oliver et al, 2000;Ciofu et al, 2005;Henrichfreise et al, 2007;Ferroni et al, 2009) and we have recently shown that even small increases in the mutation frequencies, less than 20 times the mutation frequency of PAO1, can represent an advantage for the adaptation of the strains to the antibiotic treatment (Mandsberg et al, 2009). …”

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confidence: 99%

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Genetic adaptation of Pseudomonas aeruginosa during chronic lung infection of patients with cystic fibrosis: strong and weak mutators with heterogeneous genetic backgrounds emerge in mucA and/or lasR mutants

et al. 2010

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During the chronic lung infection of patients with cystic fibrosis (CF), Pseudomonas aeruginosa can survive for long periods due to adaptive evolution mediated by genetic variation. Hypermutability is considered to play an important role in this adaptive evolution and it has been demonstrated that mutator populations are amplified in the CF lung by hitchhiking with adaptive mutations. Two of the genes that are frequently mutated in isolates from chronic infection are mucA and lasR. Loss-of-function mutations in these genes determine the phenotypic switch to mucoidy and loss of quorum sensing, which are considered hallmarks of chronic virulence. The aims of our study were to investigate (1) the genetic background of the P. aeruginosa subpopulations with non-mutator, weak or strong mutator phenotype and their dynamics during the chronic lung infection, and (2) the time sequence in which the hypermutable, mucoid and quorum-sensing-negative phenotypes emerge during chronic lung infection. For these purposes the sequences of mutS, mutL, uvrD, mutT, mutY and mutM anti-mutator genes as well as of mucA and lasR were analysed in 70 sequential P. aeruginosa isolates obtained from the respiratory secretions of 10 CF patients (one to three isolates per time point). Analysis of the genetic background of the mutator phenotype showed that mutS was the most commonly affected gene followed by mutL in isolates with strong mutator phenotype. The mutT, mutY, mutM genes were affected in isolates with low fold-changes in the mutation frequencies compared to the reference strain PAO1. Isolates with non-mutator, weak or strong mutator phenotype were represented at all time points showing co-existence of these subpopulations, which suggests parallel evolution of the various mutators in the different focal niches of infection in the CF lung. Mutations in mucA and lasR occurred earlier than mutations in the anti-mutator genes, showing that hypermutability is not a prerequisite for the acquisition of mucoidy and loss of quorum sensing, considered hallmarks of chronic virulence. Significantly higher mutation rates and MICs of ceftazidime, meropenem and ciprofloxacin were found for isolates collected late (more than 10 years) during the chronic lung infection compared to isolates collected earlier, which suggests an amplification of the mutator subpopulation by hitchhiking with development of antibiotic resistance. Similar evolutionary pathways concordant with adaptive radiation were observed in different clonal lineages of P. aeruginosa from CF patients.

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Section: Discussionsupporting

confidence: 57%

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confidence: 99%

Genetic adaptation of Pseudomonas aeruginosa during chronic lung infection of patients with cystic fibrosis: strong and weak mutators with heterogeneous genetic backgrounds emerge in mucA and/or lasR mutants

et al. 2010

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“…Thus our study demonstrates that resistance suppression is more challenging for the hypermutable strain compared with the two non-hypermutable strains, which is supported by literature reporting that hypermutation results in more difficult-to-eradicate infections. 17,21 For the 10 4 cfu/mL inoculum, ATCC 27853 and PAO1 exposed to tobramycin for short durations (1 and 4 h) had limited to no increase in PRB and for ATCC 27853 the PRB was unquantifiable for long durations of exposure (Figure 3). These results were supported by the MIC at 24 h remaining unchanged for the 1 and 4 h durations of exposure (Table 3).…”

Section: Resultsmentioning

confidence: 99%

“…5,19,20 It provides bacteria with an advantage through the ability to adapt quickly to stressful and fluctuating environments via rapidly gaining or enhancing resistance mechanisms. 15,21,22 Two pharmacokinetic/pharmacodynamic indices are most commonly used as predictors for bacterial killing by aminoglycosides, being the fAUC/MIC and the fC max /MIC. 23 -25 The fC max /MIC relies on the concentration at a single timepoint within a dosage interval.…”

Section: Introductionmentioning

confidence: 99%

Resistance suppression by high-intensity, short-duration aminoglycoside exposure against hypermutable and non-hypermutablePseudomonas aeruginosa

Rees

Bulitta

Oliver

et al. 2016

J. Antimicrob. Chemother.

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Objectives: Hypermutable bacteria are causing a drastic problem via their enhanced ability to become resistant. Our objectives were to compare bacterial killing and resistance emergence between differently shaped tobramycin concentration -time profiles at a given fAUC/MIC, and determine the tobramycin exposure durations that prevent resistance.Methods: Static concentration time -kill studies over 24 h used Pseudomonas aeruginosa WT strains (ATCC 27853 and PAO1) and hypermutable PAODmutS. fAUC/MIC values of 36, 72 and 168 were assessed at initial inocula of 10 6 and 10 4 cfu/mL (all strains) and 10 1.2 cfu/mL (PAODmutS only) in duplicate. Tobramycin was added at 0 h and removed at 1, 4, 10 or 24 h. Proportions of resistant bacteria and MICs were determined at 24 h. Mechanismbased modelling was conducted.Results: For all strains, high tobramycin concentrations over 1 and 4 h resulted in more rapid and extensive initial killing compared with 10 and 24 h exposures at a given fAUC/MIC. No resistance emerged for 1 and 4 h durations of exposure, although extensive regrowth of susceptible bacteria occurred. The 24 h duration of exposure revealed less regrowth, but tobramycin-resistant populations had completely replaced susceptible bacteria by 24 h for the 10 6 cfu/mL inoculum. The hypermutable PAODmutS showed the highest numbers of resistant bacteria. Total and resistant bacterial counts were described well by novel mechanism-based modelling.Conclusions: Extensive resistance emerged for 10 and 24 h durations of exposure, but not for shorter durations. The tobramycin concentration -time profile shape is vital for resistance prevention and should aid the introduction of optimized combination regimens.

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“…Interestingly, laboratorycultured P. aeruginosa biofilm microcolonies become highly enriched in mutators (13,60), and drug-resistant P. aeruginosa mutator populations resist invasion by drug-sensitive nonmutators, even in the absence of selection (65). Presently, our understanding of the relative contribution of mutators to adaptive genetic variation in CF CRI consists chiefly of a limited number of studies that link them statistically to an increased incidence of multiple antibiotic resistance (MAR) (21,30), decreased lung function (21,89), and the emergence of CRIspecific adaptive genotypes (58).…”

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confidence: 99%

Genotypic and Phenotypic Variation in Pseudomonas aeruginosa Reveals Signatures of Secondary Infection and Mutator Activity in Certain Cystic Fibrosis Patients with Chronic Lung Infections

et al. 2011

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Evolutionary adaptation of Pseudomonas aeruginosa to the cystic fibrosis lung is limited by genetic variation, which depends on rates of horizontal gene transfer and mutation supply. Because each may increase following secondary infection or mutator emergence, we sought to ascertain the incidence of secondary infection and genetic variability in populations containing or lacking mutators. Forty-nine strains collected over 3 years from 16 patients were phenotyped for antibiotic resistance and mutator status and were genotyped by repetitivesequence PCR (rep-PCR), pulsed-field gel electrophoresis (PFGE), and multilocus sequence typing (MLST). Though phenotypic and genetic polymorphisms were widespread and clustered more strongly within than between longitudinal series, their distribution revealed instances of secondary infection. Sequence data, however, indicated that interlineage recombination predated initial strain isolation. Mutator series were more likely to be multiply antibiotic resistant, but not necessarily more variable in their nucleotide sequences, than nonmutators. One mutator and one nonmutator series were sequenced at mismatch repair loci and analyzed for gene content using DNA microarrays. Both were wild type with respect to mutL, but mutators carried an 8-bp mutS deletion causing a frameshift mutation. Both series lacked 126 genes encoding pilins, siderophores, and virulence factors whose inactivation has been linked to adaptation during chronic infection. Mutators exhibited loss of severalfold more genes having functions related to mobile elements, motility, and attachment. A 105-kb, 86-gene deletion was observed in one nonmutator that resulted in loss of virulence factors related to pyoverdine synthesis and elements of the multidrug efflux regulon. Diminished DNA repair activity may facilitate but not be absolutely required for rapid evolutionary change.

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Effect of mutator P. aeruginosa on antibiotic resistance acquisition and respiratory function in cystic fibrosis

Cited by 54 publications

References 27 publications

Genetic adaptation of Pseudomonas aeruginosa during chronic lung infection of patients with cystic fibrosis: strong and weak mutators with heterogeneous genetic backgrounds emerge in mucA and/or lasR mutants

Genetic adaptation of Pseudomonas aeruginosa during chronic lung infection of patients with cystic fibrosis: strong and weak mutators with heterogeneous genetic backgrounds emerge in mucA and/or lasR mutants

Resistance suppression by high-intensity, short-duration aminoglycoside exposure against hypermutable and non-hypermutablePseudomonas aeruginosa

Genotypic and Phenotypic Variation in Pseudomonas aeruginosa Reveals Signatures of Secondary Infection and Mutator Activity in Certain Cystic Fibrosis Patients with Chronic Lung Infections

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