Efflux-Mediated Resistance to New Oxazolidinones and Pleuromutilin Derivatives in Escherichia coli with Class Specificities in the Resistance-Nodulation-Cell Division-Type Drug Transport Pathways

Schuster, Sabine; Vavra, Martina; Kern, Winfried V.

doi:10.1128/aac.01041-19

Cited by 11 publications

(9 citation statements)

References 19 publications

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“…In order to explore RND-type substrate pathway specificities of GEP and ZOL versus FQs, we examined the impact of AcrB porter domain mutations with known effects on the susceptibilities to other drugs. Among distal binding pocket (DB) mutations, the highest FQ susceptibility increases were achieved by F610A, which has been known to seriously impair resistance to almost all AcrB substrates except linezolid and sutezolid (14,15). Remarkably, F610A also results in significant MIC decreases of GEP but not of ZOL.…”

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confidence: 99%

New Topoisomerase Inhibitors: Evaluating the Potency of Gepotidacin and Zoliflodacin in Fluoroquinolone-Resistant Escherichia coli upon tolC Inactivation and Differentiating Their Efflux Pump Substrate Nature

Schuster

Vavra

Köser

et al. 2021

Antimicrob Agents Chemother

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Inactivating tolC in multidrug-resistant Escherichia coli with differing sequence types and quinolone resistance-determining mutations reveals remarkably potentiated activity of the first-in-class topoisomerase inhibitors gepotidacin and zoliflodacin. Differences between both structurally unrelated compounds in comparison to fluoroquinolones regarding the selectivity of E. coli RND-type transporters, efflux inhibitors, and AcrB porter domain mutations were demonstrated. The findings should reinforce efforts to develop efflux bypassing drugs and provide AcrB targets with critical relevance for this purpose.

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confidence: 99%

New Topoisomerase Inhibitors: Evaluating the Potency of Gepotidacin and Zoliflodacin in Fluoroquinolone-Resistant Escherichia coli upon tolC Inactivation and Differentiating Their Efflux Pump Substrate Nature

Schuster

Vavra

Köser

et al. 2021

Antimicrob Agents Chemother

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“…CARD analysis indicated that the antibiotic resistance of JSTW mainly comes from the efflux pump mechanism. One of the most critical is the drug‐resistant nodular cell division (RND) antibiotic efflux pump mechanism, which is the most common in Gram‐negative bacteria [37], including ade G, ade C, Tri C, mex T, sme D, cme A, and acr D. These genes can pump tetracycline antibiotics, fluoroquinolone antibiotics, triclosan, phenol antibiotics, diaminopyrimidine antibiotics, macrolide antibiotics, cephalosporins, macrolide antibiotics, fusidic acid, and aminoglycoside antibiotics. JSTW also harbors ATP binding cassette (ABC) antibiotic efflux pumps, including Tae A and msb A, which confer resistance to pleuromutilin antibiotics and nitroimidazole antibiotic.…”

Section: Resultsmentioning

confidence: 99%

Genomic insights into Pseudoalteromonas sp. JSTW coping with petroleum‐heavy metals combined pollution

Zan

et al. 2021

J Basic Microbiol

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Worldwide marine compound contamination by petroleum products and heavy metals is a burgeoning environmental concern. Pseudoalteromonas, prevalently distributed in marine environment, has been proven to degrade petroleum and plays an essential role in the fate of oil pollution under the combined pollution. Nevertheless, the research on the reference genes is still incomplete. Therefore, this study aims to thoroughly investigate the reference genes represented by Pseudoalteromonas sp. JSTW via whole‐genome sequencing. Next‐generation sequencing technology unfolded a genome of 4,026,258 bp, database including Clusters of Orthologous Groups (COG) and Kyoto Encyclopedia of Genes and Genomes (KEGG) were utilized to annotate the genes and metabolic pathways conferring to petroleum hydrocarbon degradation. The results show that common alkane and aromatic hydrocarbon degradation genes (alkB, ligB, yqhD, and ladA), chemotaxis gene (MCP, cheA, cheB, pcaY, and pcaR), heavy‐metal resistance, and biofilm genes (σ54, merC, pcoA, copB, etc.) were observed in whole‐genome sequence (WGS) of JSTW, which indicated that strain JSTW could potentially cope with combined pollution. The degradation efficiency of naphthalene in 60 h by JSTW was 99% without Cu2+ and 67% with 400 mg L−1 Cu2+. Comparative genome analysis revealed that genomes of Pseudoalteromonas lipolytica strain LEMB 39 and Pseudoalteromonas donghaensis strain HJ51 shared similarity with strain JSTW, suggesting they are also the potential degradater of petroleum hydrocarbons under combined pollution. Therefore, this study provides a WGS annotation and reveals the mechanism of response to combined pollution of Pseudoalteromonas sp. JSTW.

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“…The oxazolidinone class of antimicrobials, which includes LZD, exhibited excellent effects against gram-positive bacteria, but showed poor activity against gram-negative bacteria such as Escherichia coli, primarily due to the enhanced activity of AcrB, a RND-type efflux pump (Schumacher et al, 2007;Schuster et al, 2019). However, whether efflux pumps have a role in the resistance of gram-positive bacteria to LZD or RZD remains uncertain.…”

Section: Discussionmentioning

confidence: 99%

Radezolid Is More Effective Than Linezolid Against Planktonic Cells and Inhibits Enterococcus faecalis Biofilm Formation

et al. 2020

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The aim of this study was to compare the effects of radezolid and linezolid on planktonic and biofilm cells of Enterococcus faecalis. A total of 302 E. faecalis clinical isolates were collected, and the minimum inhibitory concentrations (MICs) of radezolid and linezolid were determined by the agar dilution method. Changes in the transcriptome of a highlevel, in vitro-induced linezolid-resistant isolate were assessed by RNA sequencing and RT-qPCR, and the roles of efflux pump-related genes were confirmed by overexpression analysis. Biofilm biomass was evaluated by crystal violet staining and the adherent cells in the biofilms were quantified according to CFU numbers. The MIC 50 /MIC 90 values of radezolid (0.25/0.50 mg/L) against the 302 E. faecalis clinical isolates were eightfold lower than those of linezolid (2/4 mg/L). The radezolid MICs against the highlevel linezolid-resistant isolates (linezolid MICs ≥ 64 mg/L) increased to ≥ 4 mg/L with mutations in the four copies of the V domain of the 23S rRNA gene. The mRNA expression level of OG1RF_12220 (mdlB2, multidrug ABC superfamily ATP-binding cassette transporter) increased in the high-level linezolid-resistant isolates, and radezolid and linezolid MICs against the linezolid-sensitive isolate increased with overexpression of OG1RF_12220. Radezolid (at 1/4 or 1/8× the MIC) inhibited E. faecalis biofilm formation to a greater extent than linezolid, which was primarily achieved through the inhibition of ahrC, esp, relA, and relQ transcription in E. faecalis. In conclusion, radezolid is more effective than linezolid against planktonic E. faecalis cells and inhibits biofilm formation by this bacterium.

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Efflux-Mediated Resistance to New Oxazolidinones and Pleuromutilin Derivatives in Escherichia coli with Class Specificities in the Resistance-Nodulation-Cell Division-Type Drug Transport Pathways

Cited by 11 publications

References 19 publications

New Topoisomerase Inhibitors: Evaluating the Potency of Gepotidacin and Zoliflodacin in Fluoroquinolone-Resistant Escherichia coli upon tolC Inactivation and Differentiating Their Efflux Pump Substrate Nature

New Topoisomerase Inhibitors: Evaluating the Potency of Gepotidacin and Zoliflodacin in Fluoroquinolone-Resistant Escherichia coli upon tolC Inactivation and Differentiating Their Efflux Pump Substrate Nature

Genomic insights into Pseudoalteromonas sp. JSTW coping with petroleum‐heavy metals combined pollution

Radezolid Is More Effective Than Linezolid Against Planktonic Cells and Inhibits Enterococcus faecalis Biofilm Formation

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