scholarly journals Environment Shapes the Accessible Daptomycin Resistance Mechanisms in Enterococcus faecium

2019 ◽  
Vol 63 (10) ◽  
Author(s):  
Amy G. Prater ◽  
Heer H. Mehta ◽  
Abigael J. Kosgei ◽  
William R. Miller ◽  
Truc T. Tran ◽  
...  
Keyword(s):  
Enterococcus Faecium ◽  
Cell Envelope ◽  
Multidrug Resistant ◽  
Resistance Mechanisms ◽  
Clinical Strain ◽  
Content Type ◽  
Component Cell ◽  
Evolutionary Trajectories ◽  
High Level ◽  
Cell Envelopes

ABSTRACT Daptomycin binds to bacterial cell membranes and disrupts essential cell envelope processes, leading to cell death. Bacteria respond to daptomycin by altering their cell envelopes to either decrease antibiotic binding to the membrane or by diverting binding away from septal targets. In Enterococcus faecalis, daptomycin resistance is typically coordinated by the three-component cell envelope stress response system, LiaFSR. Here, studying a clinical strain of multidrug-resistant Enterococcus faecium containing alleles associated with activation of the LiaFSR signaling pathway, we found that specific environments selected for different evolutionary trajectories, leading to high-level daptomycin resistance. Planktonic environments favored pathways that increased cell surface charge via yvcRS upregulation of dltABCD and mprF, causing a reduction in daptomycin binding. Alternatively, environments favoring complex structured communities, including biofilms, evolved both diversion and repulsion strategies via divIVA and oatA mutations, respectively. Both environments subsequently converged on cardiolipin synthase (cls) mutations, suggesting the importance of membrane modification across strategies. Our findings indicate that E. faecium can evolve diverse evolutionary trajectories to daptomycin resistance that are shaped by the environment to produce a combination of resistance strategies. The accessibility of multiple and different biochemical pathways simultaneously suggests that the outcome of daptomycin exposure results in a polymorphic population of resistant phenotypes, making E. faecium a recalcitrant nosocomial pathogen.

scholarly journals Environment Shapes the Accessible Daptomycin Resistance Mechanisms inEnterococcus faecium

2019 ◽  
Author(s):  
Amy G. Prater ◽  
Heer Mehtaa ◽  
Abigael J. Kosgei ◽  
William R. Miller ◽  
Truc T. Tran ◽  
...  
Keyword(s):  
Cell Envelope ◽  
Multidrug Resistant ◽  
Resistance Mechanisms ◽  
Clinical Strain ◽  
Anionic Phospholipid ◽  
Component Cell ◽  
Evolutionary Trajectories ◽  
Stress Response System ◽  
High Level ◽  
Cell Envelopes

AbstractDaptomycin binds to bacterial cell membranes and disrupts essential cell envelope processes leading to cell death. Bacteria respond to daptomycin by altering their cell envelopes to either decrease antibiotic binding to the membrane or by diverting binding away from vulnerable septal targets to remodeled anionic phospholipid membrane patches. InEnterococcus faecalis, daptomycin resistance is typically coordinated by the three-component cell-envelope-stress-response system, LiaFSR. Here, studying a clinical strain of multidrug-resistantEnterococcus faeciumcontaining alleles associated with activation of the LiaFSR signaling pathway, we found that specific environments selected for different evolutionary trajectories leading to high-level daptomycin resistance. Planktonic environments favored pathways that increased cell surface charge viayvcRSupregulation ofdltABCDandmprF, causing a reduction in daptomycin binding. Alternatively, environments favoring complex structured communities, including biofilms, evolved both diversion and repulsion strategies viadivIVAandoatAmutations, respectively. Both environments subsequently converged on cardiolipin synthase (cls) mutations, suggesting the importance of membrane modification across strategies. Our findings indicate thatE. faeciumcan evolve diverse evolutionary trajectories to daptomycin resistance that are shaped by the environment to produce a combination of resistance strategies. The accessibility of multiple and different biochemical pathways simultaneously suggests that the outcome of daptomycin exposure results in a polymorphic population of resistant phenotypes makingE. faeciuma recalcitrant pathogen.

Comparative study of multidrug-resistant Enterococcus faecium obtained from different hosts

2021 ◽  
Author(s):  
Aleksandra Trościańczyk ◽  
Aneta Nowakiewicz ◽  
Sebastian Gnat ◽  
Dominik Łagowski ◽  
Marcelina Osińska ◽  
...  
Keyword(s):  
Antimicrobial Resistance ◽  
Resistance Genes ◽  
Host Species ◽  
Enterococcus Faecium ◽  
Type Species ◽  
Animal Species ◽  
Multidrug Resistant ◽  
Content Type ◽  
Link Type ◽  
High Level

Introduction. The possible transfer of antimicrobial resistance genes between Enterococcus faecium isolates from humans and different animal species, including those not covered by monitoring programs (e.g. pet and wildlife), poses a serious threat to public health. Hypothesis/Gap Statement. Little is known about occurrence and mechanisms of phenomenon of multidrug resistance of E. faecium isolated from various host species in Poland. Aim. The aim of the study was to characterize multidrug-resistant E. faecium isolated from humans and animals (livestock, pets and wildlife) in terms of the occurrence of genetic markers determining resistance. Methodology. Bacterial isolates were tested for phenotypic resistance and the presence of genes encoding resistance to macrolides, tetracycline, aminoglycosides, aminocyclitols and phenicols as well as efflux pump (emeA), resolvase (tndX) and integrase (Int-Tn) genes. The quinolone resistance-determining regions of gyrA and parC were sequenced. Results. Human isolates of E. faecium were characterized by high-level resistance to: ciprofloxacin, enrofloxacin, erythromycin (100 %), as well, as aminoglycosides resistance (kanamycin – 100%, streptomycin – 78 %, gentamicin – 78%). Regardless of the animal species, high level of resistance of E. faecium to tetracycline (from 88–100 %), erythromycin (from 82–94 %) and kanamycin (from 36–100 %) was observed. All E. faecium isolates from wildlife were resistant to fluoroquinolones. However, full susceptibility to vancomycin was observed in all isolates tested. Phenotypic antimicrobial resistance of E. faecium was identified in the presence of the following resistance genes: erm(B) (70%), msr(A) (50 %), tet(L) (35 %), tet(K) (34 %), tet(M) (76 %), aac(6’)-Ie-aph(2″)-Ia (25%), ant(6)-Ia (31%), aph(3)-IIIa (68 %), (tndX) (23 %), and integrase gene (Int-Tn) (34 %). A correlation between an amino acid substitution at positions 83 and 87 of gyrA and position 80 of parC and the high-level fluoroquinolone resistance in E. faecium has been observed as well. Conclusion. The level and range of antimicrobial resistance and the panel of resistance determinants is comparable between E. faecium isolates, despite host species.

scholarly journals Whole-Genome Analysis of a Daptomycin-Susceptible Enterococcus faecium Strain and Its Daptomycin-Resistant Variant Arising during Therapy

2012 ◽  
Vol 57 (1) ◽  
pp. 261-268 ◽  
Author(s):  
Truc T. Tran ◽  
Diana Panesso ◽  
Hongyu Gao ◽  
Jung H. Roh ◽  
Jose M. Munita ◽  
...  
Keyword(s):  
Enterococcus Faecium ◽  
Fatty Acid Synthase ◽  
Cell Envelope ◽  
Phospholipid Metabolism ◽  
Clinical Strain ◽  
Cyclopropane Fatty Acid ◽  
Whole Genome ◽  
Whole Genome Analysis ◽  
Resistant Variant ◽  
Content Type

ABSTRACTDevelopment of daptomycin (DAP) resistance inEnterococcus faecalishas recently been associated with mutations in genes encoding proteins with two main functions: (i) control of the cell envelope stress response to antibiotics and antimicrobial peptides (LiaFSR system) and (ii) cell membrane phospholipid metabolism (glycerophosphoryl diester phosphodiesterase and cardiolipin synthase [cls]). However, the genetic bases for DAP resistance inEnterococcus faeciumare unclear. We performed whole-genome comparative analysis of a clinical strain pair, DAP-susceptibleE. faeciumS447 and its DAP-resistant derivative R446, which was recovered from a single patient during DAP therapy. By comparative whole-genome sequencing, DAP resistance in R446 was associated with changes in 8 genes. Two of these genes encoded proteins involved in phospholipid metabolism: (i) an R218Q substitution in Cls and (ii) an A292G reversion in a putative cyclopropane fatty acid synthase enzyme. The DAP-resistant derivative R446 also exhibited an S333L substitution in the putative histidine kinase YycG, a member of the YycFG system, which, similar to LiaFSR, has been involved in cell envelope homeostasis and DAP resistance in other Gram-positive cocci. Additional changes identified inE. faeciumR446 (DAP resistant) included two putative proteins involved in transport (one for carbohydrate and one for sulfate) and three enzymes predicted to play a role in general metabolism. Exchange of the “susceptible”clsallele from S447 for the “resistant” one belonging to R446 did not affect DAP susceptibility. Our results suggest that, apart from the LiaFSR system, the essential YycFG system is likely to be an important mediator of DAP resistance in someE. faeciumstrains.

scholarly journals Deletion ofliaRReverses Daptomycin Resistance in Enterococcus faecium Independent of the Genetic Background

2015 ◽  
Vol 59 (12) ◽  
pp. 7327-7334 ◽  
Author(s):  
Diana Panesso ◽  
Jinnethe Reyes ◽  
Elizabeth P. Gaston ◽  
Morgan Deal ◽  
Alejandra Londoño ◽  
...  
Keyword(s):  
Cell Membrane ◽  
Antimicrobial Peptides ◽  
Bactericidal Activity ◽  
Enterococcus Faecium ◽  
Genetic Background ◽  
Response Regulator ◽  
Regulatory System ◽  
Multidrug Resistant ◽  
Clinical Strain ◽  
Content Type

ABSTRACTWe have shown previously that changes in LiaFSR, a three-component regulatory system predicted to orchestrate the cell membrane stress response, are important mediators of daptomycin (DAP) resistance in enterococci. Indeed, deletion of the gene encoding the response regulator LiaR in a clinical strain ofEnterococcus faecalisreversed DAP resistance (DAP-R) and produced a strain hypersusceptible to antimicrobial peptides. Since LiaFSR is conserved inEnterococcus faecium, we investigated the role of LiaR in a variety of clinicalE. faeciumstrains representing the most common DAP-R genetic backgrounds. Deletion ofliaRin DAP-RE. faeciumR446F (DAP MIC of 16 μg/ml) and R497F (MIC of 24 μg/ml; harboring changes in LiaRS) strains fully reversed resistance (DAP MICs decreasing to 0.25 and 0.094 μg/ml, respectively). Moreover, DAP at concentrations of 13 μg/ml (achieved with human doses of 12 mg/kg body weight) retained bactericidal activity against the mutants. Furthermore, theliaRdeletion derivatives of these two DAP-R strains exhibited increased binding of boron-dipyrromethene difluoride (BODIPY)-daptomycin, suggesting that high-level DAP-R mediated by LiaR inE. faeciuminvolves repulsion of the calcium-DAP complex from the cell surface. In DAP-tolerant strains HOU503F and HOU515F (DAP MICs within the susceptible range but bacteria not killed by DAP concentrations of 5× the MIC), deletion ofliaRnot only markedly decreased the DAP MICs (0.064 and 0.047 μg/ml, respectively) but also restored the bactericidal activity of DAP at concentrations as low as 4 μg/ml (achieved with human doses of 4 mg/kg). Our results suggest that LiaR plays a relevant role in the enterococcal cell membrane adaptive response to antimicrobial peptides independent of the genetic background and emerges as an attractive target to restore the activity of DAP against multidrug-resistant strains.

scholarly journals Plasmid-Mediated OqxAB Is an Important Mechanism for Nitrofurantoin Resistance in Escherichia coli

2015 ◽  
Vol 60 (1) ◽  
pp. 537-543 ◽  
Author(s):  
Pak-Leung Ho ◽  
Ka-Ying Ng ◽  
Wai-U Lo ◽  
Pierra Y. Law ◽  
Eileen Ling-Yi Lai ◽  
...  
Keyword(s):  
Escherichia Coli ◽  
Efflux Pump ◽  
Geometric Mean ◽  
Resistance Mechanism ◽  
Multidrug Resistant ◽  
Resistance Mechanisms ◽  
Content Type ◽  
E Coli ◽  
High Level ◽  
Tract Infections

ABSTRACTIncreasing consumption of nitrofurantoin (NIT) for treatment of acute uncomplicated urinary tract infections (UTI) highlights the need to monitor emerging NIT resistance mechanisms. This study investigated the molecular epidemiology of the multidrug-resistant efflux geneoqxABand its contribution to nitrofurantoin resistance by usingEscherichia coliisolates originating from patients with UTI (n= 205; collected in 2004 to 2013) and food-producing animals (n= 136; collected in 2012 to 2013) in Hong Kong. TheoqxABgene was highly prevalent among NIT-intermediate (11.5% to 45.5%) and -resistant (39.2% to 65.5%) isolates but rare (0% to 1.7%) among NIT-susceptible (NIT-S) isolates. In our isolates, theoqxABgene was associated with IS26and was carried by plasmids of diverse replicon types. Multilocus sequence typing revealed that the clones ofoqxAB-positiveE. coliwere diverse. The combination ofoqxABandnfsAmutations was found to be sufficient for high-level NIT resistance. Curing ofoqxAB-carrying plasmids from 20 NIT-intermediate/resistant UTI isolates markedly reduced the geometric mean MIC of NIT from 168.9 μg/ml to 34.3 μg/ml. In the plasmid-cured variants, 20% (1/5) of isolates withnfsAmutations were NIT-S, while 80% (12/15) of isolates withoutnfsAmutations were NIT-S (P= 0.015). The presence of plasmid-basedoqxABincreased the mutation prevention concentration of NIT from 128 μg/ml to 256 μg/ml and facilitated the development of clinically important levels of nitrofurantoin resistance. In conclusion, plasmid-mediatedoqxABis an important nitrofurantoin resistance mechanism. There is a great need to monitor the dissemination of this transferable multidrug-resistant efflux pump.

scholarly journals ArmA Methyltransferase in a Monophasic Salmonella enterica Isolate from Food

2011 ◽  
Vol 55 (11) ◽  
pp. 5262-5266 ◽  
Author(s):  
Sophie A. Granier ◽  
Laura Hidalgo ◽  
Alvaro San Millan ◽  
Jose Antonio Escudero ◽  
Belen Gutierrez ◽  
...  
Keyword(s):  
16S Rrna ◽  
Salmonella Enterica ◽  
Multidrug Resistant ◽  
Broad Host Range ◽  
En Bloc ◽  
Content Type ◽  
Route Of Transmission ◽  
Amoxicillin Clavulanate ◽  
High Level ◽  
Level Resistance

ABSTRACTThe 16S rRNA methyltransferase ArmA is a worldwide emerging determinant that confers high-level resistance to most clinically relevant aminoglycosides. We report here the identification and characterization of a multidrug-resistantSalmonella entericasubspecies I.4,12:i:− isolate recovered from chicken meat sampled in a supermarket on February 2009 in La Reunion, a French island in the Indian Ocean. Susceptibility testing showed an unusually high-level resistance to gentamicin, as well as to ampicillin, expanded-spectrum cephalosporins and amoxicillin-clavulanate. Molecular analysis of the 16S rRNA methyltransferases revealed presence of thearmAgene, together withblaTEM-1,blaCMY-2, andblaCTX-M-3. All of these genes could be transferreden blocthrough conjugation intoEscherichia coliat a frequency of 10−5CFU/donor. Replicon typing and S1 pulsed-field gel electrophoresis revealed that thearmAgene was borne on an ∼150-kb broad-host-range IncP plasmid, pB1010. To elucidate howarmAhad integrated in pB1010, a PCR mapping strategy was developed for Tn1548, the genetic platform forarmA.The gene was embedded in a Tn1548-like structure, albeit with a deletion of the macrolide resistance genes, and an IS26was inserted within themelgene. To our knowledge, this is the first report of ArmA methyltransferase in food, showing a novel route of transmission for this resistance determinant. Further surveillance in food-borne bacteria will be crucial to determine the role of food in the spread of 16S rRNA methyltransferase genes worldwide.

Resistance to nitrofurantoin is an indicator of extensive drug-resistant (XDR) Enterobacteriaceae

2021 ◽  
Vol 70 (4) ◽  
Author(s):  
Balaram Khamari ◽  
Prakash Kumar ◽  
Bulagonda Eswarappa Pradeep
Keyword(s):  
Antimicrobial Agents ◽  
Efflux Pump ◽  
Treatment Options ◽  
Strong Association ◽  
Multidrug Resistant ◽  
Resistance Mechanisms ◽  
Resistant Bacteria ◽  
Drug Resistant ◽  
Content Type ◽  
Link Type

Introduction. Nitrofurantoin is one of the preferred antibiotics in the treatment of uropathogenic multidrug-resistant (MDR) infections. However, resistance to nitrofurantoin in extensively drug-resistant (XDR) bacteria has severely limited the treatment options. Gap statement. Information related to co-resistance or collateral sensitivity (CS) with reference to nitrofurantoin resistant bacteria is limited. Aim. To study the potential of nitrofurantoin resistance as an indicator of the XDR phenotype in Enterobacteriaceae . Methods. One hundred (45 nitrofurantoin-resistant, 21 intermediately resistant and 34 nitrofurantoin-susceptible) Enterobacteriaceae were analysed in this study. Antibiotic susceptibility testing (AST) against nitrofurantoin and 17 other antimicrobial agents across eight different classes was performed by using the Vitek 2.0 system. The isolates were screened for the prevalence of acquired antimicrobial resistance (AMR) and efflux pump genes by PCR. Results. In total, 51 % of nitrofurantoin-resistant and 28 % of intermediately nitrofurantoin resistant isolates exhibited XDR characteristics, while only 3 % of nitrofurantoin-sensitive isolates were XDR (P=0.0001). Significant co-resistance was observed between nitrofurantoin and other tested antibiotics (β-lactam, cephalosporin, carbapenem, aminoglycoside and tetracycline). Further, the prevalence of AMR and efflux pump genes was higher in the nitrofurantoin-resistant strains compared to the susceptible isolates. A strong association was observed between nitrofurantoin resistance and the presence of bla PER-1, bla NDM-1, bla OXA-48, ant(2) and oqxA-oqxB genes. Tigecycline (84 %) and colistin (95 %) were the only antibiotics to which the majority of the isolates were susceptible. Conclusion. Nitrofurantoin resistance could be an indicator of the XDR phenotype among Enterobacteriaceae , harbouring multiple AMR and efflux pump genes. Tigecycline and colistin are the only antibiotics that could be used in the treatment of such XDR infections. A deeper understanding of the co-resistance mechanisms in XDR pathogens and prescription of AST-based appropriate combination therapy may help mitigate this problem.

scholarly journals Emergence of Epidemic Multidrug-Resistant Enterococcus faecium from Animal and Commensal Strains

mBio ◽  
2013 ◽  
Vol 4 (4) ◽  
Author(s):  
François Lebreton ◽  
Willem van Schaik ◽  
Abigail Manson McGuire ◽  
Paul Godfrey ◽  
Allison Griggs ◽  
...  
Keyword(s):  
Enterococcus Faecium ◽  
Sequence Data ◽  
Mobile Element ◽  
Multidrug Resistant ◽  
Human Infection ◽  
Animal Origin ◽  
Loss Of Function ◽  
Content Type ◽  
Hospital Acquired Infection ◽  
Hospital Acquired

ABSTRACTEnterococcus faecium, natively a gut commensal organism, emerged as a leading cause of multidrug-resistant hospital-acquired infection in the 1980s. As the living record of its adaptation to changes in habitat, we sequenced the genomes of 51 strains, isolated from various ecological environments, to understand howE. faeciumemerged as a leading hospital pathogen. Because of the scale and diversity of the sampled strains, we were able to resolve the lineage responsible for epidemic, multidrug-resistant human infection from other strains and to measure the evolutionary distances between groups. We found that the epidemic hospital-adapted lineage is rapidly evolving and emerged approximately 75 years ago, concomitant with the introduction of antibiotics, from a population that included the majority of animal strains, and not from human commensal lines. We further found that the lineage that included most strains of animal origin diverged from the main human commensal line approximately 3,000 years ago, a time that corresponds to increasing urbanization of humans, development of hygienic practices, and domestication of animals, which we speculate contributed to their ecological separation. Each bifurcation was accompanied by the acquisition of new metabolic capabilities and colonization traits on mobile elements and the loss of function and genome remodeling associated with mobile element insertion and movement. As a result, diversity within the species, in terms of sequence divergence as well as gene content, spans a range usually associated with speciation.IMPORTANCEEnterococci, in particular vancomycin-resistantEnterococcus faecium, recently emerged as a leading cause of hospital-acquired infection worldwide. In this study, we examined genome sequence data to understand the bacterial adaptations that accompanied this transformation from microbes that existed for eons as members of host microbiota. We observed changes in the genomes that paralleled changes in human behavior. An initial bifurcation within the species appears to have occurred at a time that corresponds to the urbanization of humans and domestication of animals, and a more recent bifurcation parallels the introduction of antibiotics in medicine and agriculture. In response to the opportunity to fill niches associated with changes in human activity, a rapidly evolving lineage emerged, a lineage responsible for the vast majority of multidrug-resistantE. faeciuminfections.

scholarly journals Efficacy of Biocides Used in the Modern Food Industry To Control Salmonella enterica, and Links between Biocide Tolerance and Resistance to Clinically Relevant Antimicrobial Compounds

2012 ◽  
Vol 78 (9) ◽  
pp. 3087-3097 ◽  
Author(s):  
Orla Condell ◽  
Carol Iversen ◽  
Shane Cooney ◽  
Karen A. Power ◽  
Ciara Walsh ◽  
...  
Keyword(s):  
Salmonella Enterica ◽  
Food Industry ◽  
Multidrug Resistant ◽  
Cross Resistance ◽  
Antimicrobial Compounds ◽  
Cross Tolerance ◽  
Content Type ◽  
Food Grade ◽  
High Level

ABSTRACTBiocides play an essential role in limiting the spread of infectious disease. The food industry is dependent on these agents, and their increasing use is a matter for concern. Specifically, the emergence of bacteria demonstrating increased tolerance to biocides, coupled with the potential for the development of a phenotype of cross-resistance to clinically important antimicrobial compounds, needs to be assessed. In this study, we investigated the tolerance of a collection of susceptible and multidrug-resistant (MDR)Salmonella entericastrains to a panel of seven commercially available food-grade biocide formulations. We explored their abilities to adapt to these formulations and their active biocidal agents, i.e., triclosan, chlorhexidine, hydrogen peroxide, and benzalkonium chloride, after sequential rounds ofin vitroselection. Finally, cross-tolerance of different categories of biocidal formulations, their active agents, and the potential for coselection of resistance to clinically important antibiotics were investigated. Six of seven food-grade biocide formulations were bactericidal at their recommended working concentrations. All showed a reduced activity against both surface-dried and biofilm cultures. A stable phenotype of tolerance to biocide formulations could not be selected. Upon exposure ofSalmonellastrains to an active biocidal compound, a high-level of tolerance was selected for a number ofSalmonellaserotypes. No cross-tolerance to the different biocidal agents or food-grade biocide formulations was observed. Most tolerant isolates displayed changes in their patterns of susceptibility to antimicrobial compounds. Food industry biocides are effective against planktonicSalmonella. When exposed to sublethal concentrations of individual active biocidal agents, tolerant isolates may emerge. This emergence was associated with changes in antimicrobial susceptibilities.

scholarly journals Integrative and Conjugative Element-Mediated Azithromycin Resistance in Multidrug-Resistant Salmonella enterica Serovar Albany

2021 ◽  
Vol 65 (5) ◽  
Author(s):  
Yu-Ping Hong ◽  
Ying-Tsong Chen ◽  
You-Wun Wang ◽  
Bo-Han Chen ◽  
Ru-Hsiou Teng ◽  
...  
Keyword(s):  
Vibrio Cholerae ◽  
Salmonella Enterica ◽  
Multidrug Resistant ◽  
Content Type ◽  
Human Salmonellosis ◽  
High Level ◽  
Azithromycin Resistance ◽  
Level Resistance ◽  
Integrative And Conjugative Element

ABSTRACT We identified an erm42-carrying integrative and conjugative element, ICE_erm42, in 26.4% of multidrug-resistant Salmonella enterica serovar Albany isolates recovered from cases of human salmonellosis between 2014 and 2019 in Taiwan. ICE_erm42-carrying strains displayed high-level resistance to azithromycin, and the element could move into the phylogenetically distant species Vibrio cholerae via conjugation.

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