Overexpression of SmeDEF Efflux Pump Decreases Aminoglycoside Resistance in Stenotrophomonas maltophilia

Huang, Yi; Lin, Cheng Wen; Ning, Hsiao Chen; Lin, Yi Tsung; Chang, Yu Han; Yang, Tsuey Ching

doi:10.1128/aac.02685-16

Cited by 10 publications

(7 citation statements)

References 17 publications

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“…S1) confirmed that the two mutants, K MOX 8 and K AMI 32, hyperproduce the SmeDEF and SmeYZ efflux pumps, respectively. In K MOX 8, SmeYZ was downregulated as SmeDEF was hyperproduced, as expected given their reciprocal regulation (Huang et al, 2017). All three b-lactamase inhibitors retained full activity against these efflux pump hyperproducing mutants (Table 2) suggesting that efflux does not have a major role in the Based on these in vitro data we conclude that the bicyclic boronate 2 acts against S. maltophilia in a similar fashion to avibactam and clavulanic acid: it reverses aztreonam and, when due to L1/L2 hyperproduction, ceftazidime resistance ( Table 2).…”

Section: Resultssupporting

confidence: 68%

“…S1) confirmed that the two mutants, K MOX 8 and K AMI 32, hyperproduce the SmeDEF and SmeYZ efflux pumps, respectively. In K MOX 8, SmeYZ was downregulated as SmeDEF was hyperproduced, as expected given their reciprocal regulation (Huang et al ., ). All three β‐lactamase inhibitors retained full activity against these efflux pump hyperproducing mutants (Table ) suggesting that efflux does not have a major role in the observed variation in efficacy of the various β‐lactam/β‐lactamase inhibitor combinations.…”

Section: Resultsmentioning

confidence: 97%

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Structural/mechanistic insights into the efficacy of nonclassical β‐lactamase inhibitors against extensively drug resistant Stenotrophomonas maltophilia clinical isolates

Calvopiña

Hinchliffe

Brem

et al. 2017

Molecular Microbiology

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Clavulanic acid and avibactam are clinically deployed serine β-lactamase inhibitors, important as a defence against antibacterial resistance. Bicyclic boronates are recently discovered inhibitors of serine and some metallo β-lactamases. Here, we show that avibactam and a bicyclic boronate inhibit L2 (serine β-lactamase) but not L1 (metallo β-lactamase) from the extensively drug resistant human pathogen Stenotrophomonas maltophilia. X-ray crystallography revealed that both inhibitors bind L2 by covalent attachment to the nucleophilic serine. Both inhibitors reverse ceftazidime resistance in S. maltophilia because, unlike clavulanic acid, they do not induce L1 production. Ceftazidime/inhibitor resistant mutants hyperproduce L1, but retain aztreonam/inhibitor susceptibility because aztreonam is not an L1 substrate. Importantly, avibactam, but not the bicyclic boronate is deactivated by L1 at a low rate; the utility of avibactam might be compromised by mutations that increase this deactivation rate. These data rationalize the observed clinical efficacy of ceftazidime/avibactam plus aztreonam as combination therapy for S. maltophilia infections and confirm that aztreonam-like β-lactams plus nonclassical β-lactamase inhibitors, particularly avibactam-like and bicyclic boronate compounds, have potential for treating infections caused by this most intractable of drug resistant pathogens.

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Section: Resultssupporting

confidence: 68%

“…S1) confirmed that the two mutants, K MOX 8 and K AMI 32, hyperproduce the SmeDEF and SmeYZ efflux pumps, respectively. In K MOX 8, SmeYZ was downregulated as SmeDEF was hyperproduced, as expected given their reciprocal regulation (Huang et al ., ). All three β‐lactamase inhibitors retained full activity against these efflux pump hyperproducing mutants (Table ) suggesting that efflux does not have a major role in the observed variation in efficacy of the various β‐lactam/β‐lactamase inhibitor combinations.…”

Section: Resultsmentioning

confidence: 97%

Structural/mechanistic insights into the efficacy of nonclassical β‐lactamase inhibitors against extensively drug resistant Stenotrophomonas maltophilia clinical isolates

Calvopiña

Hinchliffe

Brem

et al. 2017

Molecular Microbiology

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“…The alteration of a single pump expression may have a downstream effect on the expression of other efflux systems ( 26 ). Thus, we imagined that a compensatory upregulation of other pumps, rather than smeYZ inactivation, may be the underlying factor responsible for ΔsmeYZ -mediated intracellular low iron levels.…”

Section: Resultsmentioning

confidence: 99%

Roles of SmeYZ, SbiAB, and SmeDEF Efflux Systems in Iron Homeostasis of Stenotrophomonas maltophilia

Chen

et al. 2022

Microbiol Spectr

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“…coli caused spectinomycin hypersensitivity (29). Overexpression of efflux pump protein genes smeDEF and smeX in Stenotrophomonas maltophilia resulted in decreased aminoglycoside resistance (30, 31). To date, there has been no clear explanation for these counterintuitive observations.…”

Section: Discussionmentioning

confidence: 99%

Network Integrative Genomic and Transcriptomic Analysis of Carbapenem-Resistant Klebsiella pneumoniae Strains Identifies Genes for Antibiotic Resistance and Virulence

et al. 2019

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Global increases in the use of carbapenems have resulted in several strains of Gram-negative bacteria acquiring carbapenem resistance, thereby limiting treatment options. Klebsiella pneumoniae is a common carbapenem-resistant pathogenic bacterium that is widely studied to identify novel antibiotic resistance mechanisms and drug targets. Antibiotic-resistant clinical isolates generally harbor many genetic alterations, and the identification of responsible mutations would provide insights into the molecular mechanisms of antibiotic resistance. We propose a method to prioritize mutated genes responsible for antibiotic resistance on the basis of expression changes in their local subnetworks, hypothesizing that mutated genes that show significant expression changes among the corresponding functionally associated genes are more likely to be involved in the carbapenem resistance. For network-based gene prioritization, we developed KlebNet (www.inetbio.org/klebnet), a genome-scale cofunctional network of K. pneumoniae genes. Using KlebNet, we reconstructed the functional modules for carbapenem resistance and virulence and identified the functional association between antibiotic resistance and virulence. Using complementation assays with the top candidate genes, we were able to validate a novel gene that negatively regulated carbapenem resistance and four novel genes that positively regulated virulence in Galleria mellonella larvae. Therefore, our study demonstrated the feasibility of network-based identification of genes required for antibiotic resistance and virulence of human-pathogenic bacteria. IMPORTANCE Klebsiella pneumoniae is a major bacterial pathogen that causes pneumonia and urinary tract infections in human. K. pneumoniae infections are treated with carbapenem, but carbapenem-resistant K. pneumoniae has been spreading worldwide. We are able to identify antimicrobial-resistant genes among mutated genes of the antibiotic-resistant clinical isolates. However, they usually harbor many mutated genes, including those that cause weak or neutral functional effects. Therefore, we need to prioritize the mutated genes to identify the more likely candidates for the follow-up functional analysis. For this study, we present a functional network of K. pneumoniae genes and propose a network-based method of prioritizing the mutated genes of the resistant clinical isolates. We also reconstructed the network-based functional modules for carbapenem resistance and virulence and retrieved the functional association between antibiotic resistance and virulence. This study demonstrated the feasibility of network-based analysis of clinical genomics data for the study of K. pneumoniae infection.

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Overexpression of SmeDEF Efflux Pump Decreases Aminoglycoside Resistance in Stenotrophomonas maltophilia

Cited by 10 publications

References 17 publications

Structural/mechanistic insights into the efficacy of nonclassical β‐lactamase inhibitors against extensively drug resistant Stenotrophomonas maltophilia clinical isolates

Structural/mechanistic insights into the efficacy of nonclassical β‐lactamase inhibitors against extensively drug resistant Stenotrophomonas maltophilia clinical isolates

Roles of SmeYZ, SbiAB, and SmeDEF Efflux Systems in Iron Homeostasis of Stenotrophomonas maltophilia

Network Integrative Genomic and Transcriptomic Analysis of Carbapenem-Resistant Klebsiella pneumoniae Strains Identifies Genes for Antibiotic Resistance and Virulence

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