Influence of acquired  -lactamases on the evolution of spontaneous carbapenem resistance in Escherichia coli

Adler, Marlen; Anjum, Mehreen; Andersson, Dan I.; Sandegren, Linus

doi:10.1093/jac/dks368

Cited by 54 publications

(76 citation statements)

References 34 publications

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“…Our study showed that the Gly-63-Val substitution in OmpR renders the expression of ompC and ompF inactive. These results are in agreement with the in vitro studies of Tängdén et al and Adler et al, which demonstrated that a single-step EnvZ-or OmpR-inactivating mutation was enough to significantly increase the MIC for ertapenem due to a subsequent reduction of OmpC and/or OmpF of up to 90% (23,24). Our report provides further evidence for the clinical relevance of OmpR change in the emergence of ertapenem resistance among E. coli clinical isolates.…”

Section: Discussionsupporting

confidence: 93%

“…An OmpR-inactivating mutation therefore might impact pathogen physiology and reduce bacterial fitness. Adler et al showed that OmpR inactivation caused a 20% reduction in growth rate (24). These results were in agreement with those obtained by Tsai et al, who showed that OmpK35/ompK36 porin deficiency in K. pneumoniae could decrease fitness and virulence (27).…”

Section: Discussionsupporting

confidence: 80%

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Structural Alteration of OmpR as a Source of Ertapenem Resistance in a CTX-M-15-Producing Escherichia coli O25b:H4 Sequence Type 131 Clinical Isolate

Dupont

Choinier

Roche

et al. 2017

Antimicrob Agents Chemother

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In this study, an ertapenem-nonsusceptible Escherichia coli isolate was investigated to determine the genetic basis for its carbapenem resistance phenotype. This clinical strain was recovered from a patient that received, 1 year previously, ertapenem to treat a cholangitis due to a carbapenem-susceptible extendedspectrum-␤-lactamase (ESBL)-producing E. coli isolate. Whole-genome sequencing of these strains was performed using Illumina and single-molecule real-time sequencing technologies. It revealed that they belonged to the ST131 clonal group, had the predicted O25b:H4 serotype, and produced the CTX-M-15 and TEM-1 ␤-lactamases. One nucleotide substitution was identified between these strains. It affected the ompR gene, which codes for a regulatory protein involved in the control of OmpC/ OmpF porin expression, creating a Gly-63-Val substitution. The role of OmpR alteration was confirmed by a complementation experiment that fully restored the susceptibility to ertapenem of the clinical isolate. A modeling study showed that the Gly-63-Val change displaced the histidine-kinase phosphorylation site. SDS-PAGE analysis revealed that the ertapenem-nonsusceptible E. coli strain had a decreased expression of OmpC/OmpF porins. No significant defect in the growth rate or in the resistance to Dictyostelium discoideum amoeba phagocytosis was found in the ertapenem-nonsusceptible E. coli isolate compared to its susceptible parental strain. Our report demonstrates for the first time that ertapenem resistance may emerge clinically from ESBL-producing E. coli due to mutations that modulate the OmpR activity.KEYWORDS OmpR, ST131, avibactam, carbapenem, envZ, ESBL, temocillin C arbapenems are broad-spectrum antibiotics usually reserved for severe lifethreatening infections. Some enterobacterial isolates have developed carbapenem resistance, which resulted in limited options for the treatment of infections caused by these organisms. Except for the members of the Proteeae tribe, carbapenem resistance in Enterobacteriaceae is almost always attributable to the production of ␤-lactamases, which can be distinguished according to their carbapenemase activity. True carbapenemases (e.g., KPC, OXA-48, and metallo-␤-lactamases [MBLs]) confer per se resistance to carbapenems, whereas extended-spectrum ␤-lactamases (ESBLs) and AmpC-type enzymes require an additional mechanism of resistance, such as decrease in the uptake

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Section: Discussionsupporting

confidence: 93%

Section: Discussionsupporting

confidence: 80%

Structural Alteration of OmpR as a Source of Ertapenem Resistance in a CTX-M-15-Producing Escherichia coli O25b:H4 Sequence Type 131 Clinical Isolate

Dupont

Choinier

Roche

et al. 2017

Antimicrob Agents Chemother

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“…Silver resistance was, however, easily induced in vitro, and in some cases this was associated with loss of porins and/or altered susceptibility to antibiotics. Loss of porins is known to cause decreased susceptibility to beta-lactams (18,32,40). A problematic decrease in susceptibility to piperacillin-tazobactam, one of the few treatment alternatives left in more severe infections caused by ESBL-producing E. coli, was noticed.…”

Section: Discussionmentioning

confidence: 99%

Silver Resistance Genes Are Overrepresented among Escherichia coli Isolates with CTX-M Production

Sütterlin

Edquist

Sandegren

et al. 2014

Appl Environ Microbiol

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Members of the Enterobacteriaceae with extended-spectrum beta-lactamases (ESBLs) of the CTX-M type have disseminated rapidly in recent years and have become a threat to public health. In parallel with the CTX-M type expansion, the consumption and widespread use of silver-containing products has increased. To determine the carriage rates of silver resistance genes in different Escherichia coli populations, the presence of three silver resistance genes (silE, silP, and silS) and genes encoding CTX-M-, TEM-, and SHV-type enzymes were explored in E. coli isolates of human (n ‫؍‬ 105) and avian (n ‫؍‬ 111) origin. The antibiotic profiles were also determined. Isolates harboring CTX-M genes were further characterized, and phenotypic silver resistance was examined. The silE gene was present in 13 of the isolates. All of them were of human origin. Eleven of these isolates harbored ESBLs of the CTX-M type (P ‫؍‬ 0.007), and eight of them were typed as CTX-M-15 and three as CTX-M-14. None of the silE-positive isolates was related to the O25b-ST131 clone, but 10 out of 13 belonged to the ST10 or ST58 complexes. Phenotypic silver resistance (silver nitrate MIC > 512 mg/liter) was observed after silver exposure in 12 of them, and a concomitant reduced susceptibility to piperacillin-tazobactam developed in three. In conclusion, 12% of the human E. coli isolates but none of the avian isolates harbored silver resistance genes. This indicates another route for or level of silver exposure for humans than that caused by common environmental contamination. Since silE-positive isolates were significantly more often found in CTX-M-positive isolates, it is possible that silver may exert a selective pressure on CTX-M-producing E. coli isolates.

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“…A number of biochemical and genetic evidence supports the idea that many enzymes can catalyze adventitious secondary reactions (i.e., they have promiscuous activities), and that these activities are sometimes high enough to contribute to the fitness of the organism with the proper selective pressure and when overexpressed (Copley 2003;Khersonsky et al 2006;Khersonsky and Tawfik 2010). For example, various b-lactamases, with primary penicillin-hydrolyzing activities, can also contribute to decreased susceptibility toward other classes of b-lactam antibiotics Adler et al 2013). Patrick et al (2007) identified a number of E. coli genes that, when overexpressed, could complement the auxotrophy caused by lack of another gene.…”

Section: Innovationmentioning

confidence: 99%

Evolution of New Functions De Novo and from Preexisting Genes

Andersson

Jerlström-Hultqvist

Näsvall

2015

Cold Spring Harb Perspect Biol

133

107

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Influence of acquired -lactamases on the evolution of spontaneous carbapenem resistance in Escherichia coli

Cited by 54 publications

References 34 publications

Structural Alteration of OmpR as a Source of Ertapenem Resistance in a CTX-M-15-Producing Escherichia coli O25b:H4 Sequence Type 131 Clinical Isolate

Structural Alteration of OmpR as a Source of Ertapenem Resistance in a CTX-M-15-Producing Escherichia coli O25b:H4 Sequence Type 131 Clinical Isolate

Silver Resistance Genes Are Overrepresented among Escherichia coli Isolates with CTX-M Production

Evolution of New Functions De Novo and from Preexisting Genes

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