LmrS Is a Multidrug Efflux Pump of the Major Facilitator Superfamily from
            <i>Staphylococcus aureus</i>

Floyd, Jody L.; Smith, Kenneth P.; Kumar, Sanath; Floyd, Jared T.; Varela, Manuel F.

doi:10.1128/aac.00580-10

Cited by 159 publications

(117 citation statements)

References 47 publications

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“…The only clear nonribosomal linezolid resistance mechanism reported is related to mutations causing increased expression of ABC transporter genes in Streptococcus pneumoniae (3,19). It has also been shown that Staphylococcus aureus possesses a gene for a majorfacilitator-superfamily-type multidrug efflux pump named LmrS that is capable of extruding linezolid (21).…”

Section: Linezolidmentioning

confidence: 99%

Resistance to Linezolid Caused by Modifications at Its Binding Site on the Ribosome

Long

Vester

2012

Antimicrob Agents Chemother

313

195

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Linezolid is an oxazolidinone antibiotic in clinical use for the treatment of serious infections of resistant Gram-positive bacteria. It inhibits protein synthesis by binding to the peptidyl transferase center on the ribosome. Almost all known resistance mechanisms involve small alterations to the linezolid binding site, so this review will therefore focus on the various changes that can adversely affect drug binding and confer resistance. High-resolution structures of linezolid bound to the 50S ribosomal subunit show that it binds in a deep cleft that is surrounded by 23S rRNA nucleotides. Mutation of 23S rRNA has for some time been established as a linezolid resistance mechanism. Although ribosomal proteins L3 and L4 are located further away from the bound drug, mutations in specific regions of these proteins are increasingly being associated with linezolid resistance. However, very little evidence has been presented to confirm this. Furthermore, recent findings on the Cfr methyltransferase underscore the modification of 23S rRNA as a highly effective and transferable form of linezolid resistance. On a positive note, detailed knowledge of the linezolid binding site has facilitated the design of a new generation of oxazolidinones that show improved properties against the known resistance mechanisms. LINEZOLID

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Section: Linezolidmentioning

confidence: 99%

Resistance to Linezolid Caused by Modifications at Its Binding Site on the Ribosome

Long

Vester

2012

Antimicrob Agents Chemother

313

195

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“…In fact, alterations in these ribosomal proteins are currently often observed among staphylococcal isolates, especially among coagulase-negative staphylococci, demonstrating a shift in the epidemiology of linezolid-nonsusceptible isolates and associated resistance mechanisms (2). Efflux-pump mechanisms have also been implicated as a linezolid resistance mechanism (5), and a plasmid-mediated gene (transferable) was recently described (6).…”

mentioning

confidence: 99%

Detection of a New cfr -Like Gene, cfr (B), in Enterococcus faecium Isolates Recovered from Human Specimens in the United States as Part of the SENTRY Antimicrobial Surveillance Program

Deshpande

Ashcraft

Kahn

et al. 2015

Antimicrob Agents Chemother

127

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Two linezolid-resistant Enterococcus faecium isolates (MICs, 8 g/ml) from unique patients of a medical center in New Orleans were included in this study. Isolates were initially investigated for the presence of mutations in the V domain of 23S rRNA genes and L3, L4, and L22 ribosomal proteins, as well as cfr. Isolates were subjected to pulsed-field gel electrophoresis (just one band difference), and one representative strain was submitted to whole-genome sequencing. Gene location was also determined by hybridization, and cfr genes were cloned and expressed in a Staphylococcus aureus background. The two isolates had one out of six 23S rRNA alleles mutated (G2576T), had wild-type L3, L4, and L22 sequences, and were positive for a cfr-like gene. The sequence of the protein encoded by the cfr-like gene was most similar (99.7%) to that found in Peptoclostridium difficile, which shared only 74.9% amino acid identity with the proteins encoded by genes previously identified in staphylococci and non-faecium enterococci and was, therefore, denominated Cfr(B). When expressed in S. aureus, the protein conferred a resistance profile similar to that of Cfr. Two copies of cfr(B) were chromosomally located and embedded in a Tn6218 similar to the cfr-carrying transposon described in P. difficile. This study reports the first detection of cfr genes in E. faecium clinical isolates in the United States and characterization of a new cfr variant, cfr(B). cfr(B) has been observed in mobile genetic elements in E. faecium and P. difficile, suggesting potential for dissemination. However, further analysis is necessary to access the resistance levels conferred by cfr(B) when expressed in enterococci.

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“…For example, the aerobic MIC of php was found to vary between 4 g mL −1 (S. epidermidis) and 500 g mL −1 (S. aureus ATCC 29213) [52], and in another study the death percentage of S. aureus ATCC 26923 in 20 g php mL −1 was 32% [114]. It is conceivable that, as discussed above for S. aureus, pyp exerted its intrinsic effect on the manure microbiota through inhibition of a MDR efflux pump, such as LmrS, MdeA, and possibly NorA, as these and their homologues occur in B. subtilis, a major component of MicroSource S, and are widespread among other low mol percentage guanine-cytosine Gram-positive (phylum Firmicutes) bacteria [27,81,97,100,[115][116][117], the predominant culturable anaerobic microorganisms from swine manure [73,118,119].…”

Section: Discussionmentioning

confidence: 99%

“…Thirdly, efflux-mediated antimicrobial resistance is controlled by the metabolic condition of bacteria and can be altered by a switch from an aerobic to an anaerobic metabolism through the influence of metabolically integrated global regulators, different endogenous cellular metabolites, such as ROS from aerobic respiration or anaerobic fermentation end products which often times are the natural pump substrates, and an altered transmembrane electrochemical proton gradient as energy source for secondary active transporters [27,28,32,80]. Hence, it can be presumed that the higher level of induced resistance in S. aureus under anaerobic conditions was contingent on a switch from glycolysis, the pentose phosphate pathway and ROS generating tricarboxylic acid cycle under aerobiosis to anaerobic glucose fermentation and ATPase-mediated proton efflux, generating a greater motive force for erythromycin-proton antiporters [28,80,94], such as LmrS, MdeA, Mef(A), and conceivably NorA [27,32,[95][96][97].…”

Section: Discussionmentioning

confidence: 99%

“…faecalis bearing the NorA homologue EmeA (Figures 3(a) and 3(c)). The S. aureus genome comprises at least 30 genes for putative drug transporters, and approximately 17 of these encode MDR efflux pumps, most of which are still unknown [98,99] and two of which, LmrS and MdeA, contribute to erythromycin resistance [27,32,97,100] and are therefore possible candidates for inhibition by pyp. Pyp in combination with erythromycin only partially reversed high-level resistance of S. aureus and did not completely inhibit its growth (Figures 3(a), 3(c), and 5(c)).…”

Section: Discussionmentioning

confidence: 99%

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Effects of Chlorophyll-Derived Efflux Pump Inhibitor Pheophorbideaand Pyropheophorbideaon Growth and Macrolide Antibiotic Resistance of Indicator and Anaerobic Swine Manure Bacteria

Kraatz

Whitehead

Cotta

et al. 2014

International Journal of Antibiotics

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Natural plant compounds, such as the chlorophyll a catabolites pheophorbide a (php) and pyropheophorbide a (pyp), are potentially active in the gastrointestinal tracts and manure of livestock as antimicrobial resistance-modifying agents through inhibition of bacterial efflux pumps. To investigate whether php, a known efflux pump inhibitor, and pyp influence bacterial resistance, we determined their long-term effects on the MICs of erythromycin for reference strains of clinically relevant indicator bacteria with macrolide or multidrug resistance efflux pumps. Pyp reduced the final MIC endpoint for Staphylococcus (S.) aureus and Escherichia (E.) coli by up to 1536 and 1024 g erythromycin mL −1 or 1.4-and 1.2-fold, respectively. Estimation of growth parameters of S. aureus revealed that pyp exerted an intrinsic inhibitory effect under anaerobic conditions and was synergistically active, thereby potentiating the effect of erythromycin and partially reversing high-level erythromycin resistance. Anaerobe colony counts of total and erythromycin-resistant bacteria from stored swine manure samples tended to be lower in the presence of pyp. Tylosin, php, and pyp were not detectable by HPLC in the manure or medium. This is the first study showing that pyp affects growth and the level of sensitivity to erythromycin of S. aureus, E. coli, and anaerobic manure bacteria.

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LmrS Is a Multidrug Efflux Pump of the Major Facilitator Superfamily from Staphylococcus aureus

Cited by 159 publications

References 47 publications

Resistance to Linezolid Caused by Modifications at Its Binding Site on the Ribosome

Resistance to Linezolid Caused by Modifications at Its Binding Site on the Ribosome

Detection of a New cfr -Like Gene, cfr (B), in Enterococcus faecium Isolates Recovered from Human Specimens in the United States as Part of the SENTRY Antimicrobial Surveillance Program

Effects of Chlorophyll-Derived Efflux Pump Inhibitor Pheophorbideaand Pyropheophorbideaon Growth and Macrolide Antibiotic Resistance of Indicator and Anaerobic Swine Manure Bacteria

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