Resistance to ceftazidime in Escherichia coli associated with AcrR, MarR and PBP3 mutations and overexpression of sdiA

Tavío, María M.; Aquili, Virginia; Vila, Jordi

doi:10.1099/jmm.0.063727-0

Cited by 15 publications

(14 citation statements)

References 67 publications

(117 reference statements)

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“…This module is thought to function as an intramolecular chaperone, and thus mutations in it could contribute to resistance by influencing the folding or stability of the whole protein [46]. Mutations in this module, indeed, have been reported in E. coli to confer resistance to ceftazidime, a b-lactam antibiotic structurally very close to CTX [47].…”

Section: (C) Genotypic Characterization Of Evolved Lineagesmentioning

confidence: 99%

Bypass of genetic constraints during mutator evolution to antibiotic resistance

2015

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Genetic constraints can block many mutational pathways to optimal genotypes in real fitness landscapes, yet the extent to which this can limit evolution remains to be determined. Interestingly, mutator bacteria elevate only specific types of mutations, and therefore could be very sensitive to genetic constraints. Testing this possibility is not only clinically relevant, but can also inform about the general impact of genetic constraints in adaptation. Here, we evolved 576 populations of two mutator and one wild-type Escherichia coli to doubling concentrations of the antibiotic cefotaxime. All strains carried TEM-1, a b-lactamase enzyme well known by its low availability of mutational pathways. Crucially, one of the mutators does not elevate any of the relevant first-step mutations known to improve cefatoximase activity. Despite this, both mutators displayed a similar ability to evolve more than 1000-fold resistance. Initial adaptation proceeded in parallel through general multi-drug resistance mechanisms. High-level resistance, in contrast, was achieved through divergent paths; with the a priori inferior mutator exploiting alternative mutational pathways in PBP3, the target of the antibiotic. These results have implications for mutator management in clinical infections and, more generally, illustrate that limits to natural selection in real organisms are alleviated by the existence of multiple loci contributing to fitness.

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Section: (C) Genotypic Characterization Of Evolved Lineagesmentioning

confidence: 99%

Bypass of genetic constraints during mutator evolution to antibiotic resistance

2015

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“…4). Indeed, one in vitro-selected high-level ceftazidime-resistant mutant (128-fold MIC increase) had OmpF loss and increased expression levels of acrB, acrD, and acrF with multiple mutations in acrR, marR, and the gene for penicillin-binding protein 3 and overexpressed sdiA, while another mutant with low-level ceftazidime resistance (4-fold MIC increase) showed only increased acrB expression levels due to an acrR mutation (755).…”

Section: E Coli Efflux Pumpsmentioning

confidence: 99%

The Challenge of Efflux-Mediated Antibiotic Resistance in Gram-Negative Bacteria

2015

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SUMMARY The global emergence of multidrug-resistant Gram-negative bacteria is a growing threat to antibiotic therapy. The chromosomally encoded drug efflux mechanisms that are ubiquitous in these bacteria greatly contribute to antibiotic resistance and present a major challenge for antibiotic development. Multidrug pumps, particularly those represented by the clinically relevant AcrAB-TolC and Mex pumps of the resistance-nodulation-division (RND) superfamily, not only mediate intrinsic and acquired multidrug resistance (MDR) but also are involved in other functions, including the bacterial stress response and pathogenicity. Additionally, efflux pumps interact synergistically with other resistance mechanisms (e.g., with the outer membrane permeability barrier) to increase resistance levels. Since the discovery of RND pumps in the early 1990s, remarkable scientific and technological advances have allowed for an in-depth understanding of the structural and biochemical basis, substrate profiles, molecular regulation, and inhibition of MDR pumps. However, the development of clinically useful efflux pump inhibitors and/or new antibiotics that can bypass pump effects continues to be a challenge. Plasmid-borne efflux pump genes (including those for RND pumps) have increasingly been identified. This article highlights the recent progress obtained for organisms of clinical significance, together with methodological considerations for the characterization of MDR pumps.

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“…Subsequent expression of the transcriptional activator MarA then leads to upregulation of a multidrug efflux system. Moreover, loss of function mutations in MarR or MarR homologues are known to cause clinically relevant drug-resistant phenotypes, in particular towards fluoroquinolones [66–69]. While these results potentially implicate the mar locus in JBIR-100 resistance, the general nature of this resistance mechanism means mutation of yusO is unlikely to give meaningful insight into biological target(s) of JBIR-100.…”

Section: Resultsmentioning

confidence: 99%

Biological characterization of the hygrobafilomycin antibiotic JBIR-100 and bioinformatic insights into the hygrolide family of natural products

Molloy

Tietz

Blair

et al. 2016

Bioorganic & Medicinal Chemistry

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The hygrolides, a family of 16-member-ring-containing plecomacrolides produced by Actinobacteria, exhibit numerous reported bioactivities. Using HR-MS/MS, nucleophilic 1,4-addition-based labeling, NMR, and bioinformatic analysis, we identified Streptomyces varsoviensis as a novel producer of JBIR-100, a fumarate-containing hygrolide, and elucidated the previously unknown stereochemistry of the natural product. We investigated the antimicrobial activity of JBIR-100, with preliminary insight into mode of action indicating that it perturbs the membrane of Bacillus subtilis. S. varsoviensis is known to produce compounds from multiple hygrolide sub-families, namely hygrobafilomycins (JBIR-100 and hygrobafilomycin) and bafilomycins (bafilomycin C1 and D). In light of this, we identified the biosynthetic gene cluster for JBIR-100, which, to our knowledge, represents the first reported for a hygrobafilomycin. Finally, we performed a bioinformatic analysis of the hygrolide family, describing clusters from known and predicted producers. Our results indicate that potential remains for the Actinobacteria to yield novel hygrolide congeners, perhaps with differing biological activities.

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Resistance to ceftazidime in Escherichia coli associated with AcrR, MarR and PBP3 mutations and overexpression of sdiA

Cited by 15 publications

References 67 publications

Bypass of genetic constraints during mutator evolution to antibiotic resistance

Bypass of genetic constraints during mutator evolution to antibiotic resistance

The Challenge of Efflux-Mediated Antibiotic Resistance in Gram-Negative Bacteria

Biological characterization of the hygrobafilomycin antibiotic JBIR-100 and bioinformatic insights into the hygrolide family of natural products

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