Development of carbapenem resistance in Pseudomonas aeruginosa is associated with OprD polymorphisms, particularly the amino acid substitution at codon 170

Shu, Jwu-Ching; Kuo, An-Jing; Su, Lin‐Hui; Liu, Tsui-Ping; Lee, Ming-Hsun; Su, I-Ning; Wu, Tsu‐Lan

doi:10.1093/jac/dkx158

Cited by 32 publications

(27 citation statements)

References 30 publications

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“…Other resistance mechanisms, like the reduced expression of oprD and overexpression of efflux pumps, were not specifically addressed, but the possibility of their contribution to resistance cannot be finally excluded. Analysis of the OprD sequence and comparison to the literature did not provide any clear evidence that OprD of ID40 is dysfunctional (25)(26)(27)(28).…”

Section: Resultsmentioning

confidence: 81%

Identification of Drug Resistance Determinants in a Clinical Isolate of Pseudomonas aeruginosa by High-Density Transposon Mutagenesis

Sonnabend

Klein

Beier³

et al. 2020

Antimicrob Agents Chemother

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With the aim to identify potential new targets to restore antimicrobial susceptibility of multidrug-resistant (MDR) Pseudomonas aeruginosa isolates, we generated a high-density transposon (Tn) insertion mutant library in an MDR P. aeruginosa bloodstream isolate (isolate ID40). The depletion of Tn insertion mutants upon exposure to cefepime or meropenem was measured in order to determine the common resistome for these clinically important antipseudomonal β-lactam antibiotics. The approach was validated by clean deletions of genes involved in peptidoglycan synthesis/recycling, such as the genes for the lytic transglycosylase MltG, the murein (Mur) endopeptidase MepM1, the MurNAc/GlcNAc kinase AmgK, and the uncharacterized protein YgfB, all of which were identified in our screen as playing a decisive role in survival after treatment with cefepime or meropenem. We found that the antibiotic resistance of P. aeruginosa can be overcome by targeting usually nonessential genes that turn essential in the presence of therapeutic concentrations of antibiotics. For all validated genes, we demonstrated that their deletion leads to the reduction of ampC expression, resulting in a significant decrease in β-lactamase activity, and consequently, these mutants partly or completely lost resistance against cephalosporins, carbapenems, and acylaminopenicillins. In summary, the determined resistome may comprise promising targets for the development of drugs that may be used to restore sensitivity to existing antibiotics, specifically in MDR strains of P. aeruginosa.

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Section: Resultsmentioning

confidence: 81%

Identification of Drug Resistance Determinants in a Clinical Isolate of Pseudomonas aeruginosa by High-Density Transposon Mutagenesis

Sonnabend

Klein

Beier³

et al. 2020

Antimicrob Agents Chemother

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“…This result is consistent with previous studies ( Wang et al, 2010 ; Rojo-Bezares et al, 2014 ). However, a recent study demonstrates that the common polymorphism at codon 170 (F107L), is associated with reduced oprD expression and the potential to develop carbapenem resistance in PAO1 ( Shu et al, 2017 ). This most common mutation of F107L was also found in all of the 8 isolates with amino acid substitutions in our study.…”

Section: Discussionmentioning

confidence: 99%

Molecular Typing and Carbapenem Resistance Mechanisms of Pseudomonas aeruginosa Isolated From a Chinese Burn Center From 2011 to 2016

et al. 2018

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Pseudomonas aeruginosa is the leading cause of infection in burn patients. The increasing carbapenem resistance of P. aeruginosa has become a serious challenge to clinicians. The present study investigated the molecular typing and carbapenem resistance mechanisms of 196 P. aeruginosa isolates from the bloodstream and wound surface of patients in our burn center over a period of 6 years. By multilocus sequence typing (MLST), a total of 58 sequence types (STs) were identified. An outbreak of ST111, a type that poses a high international risk, occurred in 2014. The isolates from wound samples of patients without bacteremia were more diverse and more susceptible to antibiotics than strains collected from the bloodstream or the wound surface of patients with bacteremia. Importantly, a large proportion of the patients with multisite infection (46.51%) were simultaneously infected by different STs in the bloodstream and wound surface. Antimicrobial susceptibility testing of these isolates revealed high levels of resistance to carbapenems, with 35.71% susceptibility to imipenem and 32.14% to meropenem. To evaluate mechanisms associated with carbapenem resistance, experiments were conducted to determine the prevalence of carbapenemase genes, detect alterations of the oprD porin gene, and measure expression of the ampC β-lactamase gene and the mexB multidrug efflux gene. The main mechanism associated with carbapenem resistance was mutational inactivation of oprD (88.65%), accompanied by overexpression of ampC (68.09%). In some cases, oprD was inactivated by insertion sequence element IS1411, which has not been found previously in P. aeruginosa. These findings may help control nosocomial P. aeruginosa infections and improve clinical practice.

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“…It is surprising that the Xpert ® Carba-R assay detected no carbapenemase-encoding genes among the carbapenem non-susceptible P. aeruginosa . According to previous studies on carbapenem-resistant P. aeruginosa in Taiwan, the overproduction of active efflux pump and OprD polymorphisms were the major mechanisms of resistance,26,27 which might explain the negative results.…”

Section: Discussionmentioning

confidence: 99%

Antimicrobial activities of ceftazidime–avibactam, ceftolozane–tazobactam, and other agents against Escherichia coli, Klebsiella pneumoniae, and Pseudomonas aeruginosa isolated from intensive care units in Taiwan: results from the Surveillance of Multicenter Antimicrobial Resistance in Taiwan in 2016

Liao¹,

Lee²,

Tang³

et al. 2019

IDR

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The aim of this study was to investigate the in vitro antimicrobial susceptibilities of clinically important Gram-negative bacteria from seven intensive care units in Taiwan in 2016. Materials and methods: In total, 300 non-duplicate isolates of Escherichia coli (n=100), Klebsiella pneumoniae (n=100), and Pseudomonas aeruginosa (n=100) collected from 300 patients were studied. The minimum inhibitory concentrations (MICs) of these isolates to antimicrobial agents were determined using the broth microdilution method. Carbapenemaseencoding genes (bla KPC , bla NDM , bla IMP , bla VIM , and bla OXA-48-like) were studied for the isolates that were not susceptible to any carbapenems. Sequencing analysis of the mcr genes (mcr-1-5) was conducted for all isolates with colistin MICs ≥4 mg/L. Results: Ertapenem non-susceptibility was detected in 3% (n=3) E. coli and 12% (n=12) K. pneumoniae isolates. The susceptibility rates of imipenem, ceftazidime-avibactam (CAZ-AVB), and ceftolozane-tazobactam (CLZ-TAZ) were 99%, 99%, and 88%, respectively, for E. coli, 91%, 100%, and 80%, respectively, for K. pneumoniae, and 66%, 91%, and 93%, respectively, for P. aeruginosa. Carbapenemase-encoding genes were not detected in E. coli, were detected in four (33.3%) K. pneumoniae isolates that were not susceptible to ertapenem (three harboring bla KPC and one harboring bla OXA-48-like), and were not detected in P. aeruginosa isolates that were not susceptible to imipenem. One K. pneumoniae isolate was resistant to colistin (MIC 4 mg/L) and negative for mcr genes. Conclusion: CAZ-AVB exhibited excellent activity against carbapenem-resistant Enterobacteriaceae, and CLZ-TAZ exhibited good activity against imipenem-resistant P. aeruginosa.

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Development of carbapenem resistance in Pseudomonas aeruginosa is associated with OprD polymorphisms, particularly the amino acid substitution at codon 170

Abstract: OprD polymorphisms, particularly the F170L substitution and the specific shortening in loop 7, appear to determine the potential for P. aeruginosa to develop carbapenem resistance.

Cited by 32 publications

References 30 publications

Identification of Drug Resistance Determinants in a Clinical Isolate of Pseudomonas aeruginosa by High-Density Transposon Mutagenesis

Identification of Drug Resistance Determinants in a Clinical Isolate of Pseudomonas aeruginosa by High-Density Transposon Mutagenesis

Molecular Typing and Carbapenem Resistance Mechanisms of Pseudomonas aeruginosa Isolated From a Chinese Burn Center From 2011 to 2016

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