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.

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 1192. Identification of a Novel Enterobacter cloacae Isolate Producing an IMP-13 Metallo-β-Lactamase

2018 ◽  
Vol 5 (suppl_1) ◽  
pp. S360-S361
Author(s):  
Muhammad Bilal Abid ◽  
Blake Buchan ◽  
Nathan Ledeboer ◽  
L Silvia Munoz-Price ◽  
Mary Beth Graham
Keyword(s):  
Clinical Success ◽  
Multidrug Resistant ◽  
Resistance Mechanisms ◽  
Stage Iiic ◽  
Travel History ◽  
Healthcare Settings ◽  
High Level ◽  
Culture Positive ◽  
Broth Dilution ◽  
Level Resistance

Abstract Background Metallo-β-lactamases (MBLs) have been identified as emerging resistance determinants in Enterobacteriaceae, A. baumanii, and P. aeruginosa. Early identification of carbapenemase-producing organisms (CPOs) is essential to prevent dissemination within healthcare settings. We report a case of a patient who was blood culture positive for a multidrug-resistant E. cloacae which was subsequently found to be positive for the MBL blaIMP-13. Methods A 74-year-old female, with no significant past medical or travel history, developed sepsis 2 days after undergoing debulking surgery for stage IIIc ovarian carcinoma. Blood cultures were positive for Gram-negative bacilli and the organisms identified as Enterobacter spp. with blaIMP MBL (Verigene). Antimicrobial susceptibility testing demonstrated high-level resistance to all penicillins, ureidopenicillins, cephalosporins, and β-lactam/inhibitor antibiotics, and susceptibility to colistin, tigecycline, and monobactams. Results Further testing using micro-broth dilution, BD phoenix, and Etest, demonstrated susceptible MICs to meropenem and imipenem, with intermediate to resistant MICs to ertapenem. The patient was treated with a combination therapy of amikacin, aztreonam, and ceftazidime-avibactam and responded clinically. Per standard protocol, the organism was sent to WI Laboratory of Hygiene for further characterization. Phenotypic testing using the modified carbapenem inactivation test (mCIM) was positive, indicating the presence of a carbapenemase; however, results using Xpert CarbaR (Cepheid) were negative. Subsequent sequencing of the isolate confirmed the presence of blaIMP-13. Conclusion This was an important case for several reasons. First, blaIMP-13 is historically reported in Pseudomonas aeruginosa. Indeed, this was the first report of Enterobacteriaceae harboring blaIMP in WI. Second, it had unique susceptibility pattern to carbapenems and was not detected by the CarbaR. Third, these data demonstrate clinical success in treating an MBL CPO with a combination anti-microbial regimen, based on an understanding of resistance mechanisms involved. This report calls for more vigilant screening for CPO using both phenotypic and genotypic methods. Disclosures N. Ledeboer, Luminex: Consultant, Consulting fee.

scholarly journals Antimicrobial sensing coupled with cell membrane remodeling mediates antibiotic resistance and virulence inEnterococcus faecalis

2019 ◽  
Vol 116 (52) ◽  
pp. 26925-26932 ◽  
Author(s):  
Ayesha Khan ◽  
Milya Davlieva ◽  
Diana Panesso ◽  
Sandra Rincon ◽  
William R. Miller ◽  
...  
Keyword(s):  
Stress Response ◽  
Response Regulator ◽  
Cell Envelope ◽  
Multidrug Resistant ◽  
Innate Immune ◽  
Evolutionary Strategies ◽  
Phospholipid Content ◽  
Anionic Phospholipid ◽  
Extracellular Milieu ◽  
Terminal Domain

Bacteria have developed several evolutionary strategies to protect their cell membranes (CMs) from the attack of antibiotics and antimicrobial peptides (AMPs) produced by the innate immune system, including remodeling of phospholipid content and localization. Multidrug-resistantEnterococcus faecalis,an opportunistic human pathogen, evolves resistance to the lipopeptide daptomycin and AMPs by diverting the antibiotic away from critical septal targets using CM anionic phospholipid redistribution. The LiaFSR stress response system regulates this CM remodeling via the LiaR response regulator by a previously unknown mechanism. Here, we characterize a LiaR-regulated protein, LiaX, that senses daptomycin or AMPs and triggers protective CM remodeling. LiaX is surface exposed, and in daptomycin-resistant clinical strains, both LiaX and the N-terminal domain alone are released into the extracellular milieu. The N-terminal domain of LiaX binds daptomycin and AMPs (such as human LL-37) and functions as an extracellular sentinel that activates the cell envelope stress response. The C-terminal domain of LiaX plays a role in inhibiting the LiaFSR system, and when this domain is absent, it leads to activation of anionic phospholipid redistribution. Strains that exhibit LiaX-mediated CM remodeling and AMP resistance show enhanced virulence in theCaenorhabditis elegansmodel, an effect that is abolished in animals lacking an innate immune pathway crucial for producing AMPs. In conclusion, we report a mechanism of antibiotic and AMP resistance that couples bacterial stress sensing to major changes in CM architecture, ultimately also affecting host–pathogen interactions.

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 Relevance of resistance levels to carbapenems and integron-borne bla IMP-1, bla IMP-7, bla IMP-10 and bla VIM-2 in clinical isolates of Pseudomonas aeruginosa

2009 ◽  
Vol 58 (8) ◽  
pp. 1080-1085 ◽  
Author(s):  
Wei-Hua Zhao ◽  
Gelin Chen ◽  
Ribu Ito ◽  
Zhi-Qing Hu
Keyword(s):  
Pseudomonas Aeruginosa ◽  
Resistance Genes ◽  
Gene Cassette ◽  
Multidrug Resistant ◽  
Resistance Mechanisms ◽  
Clinical Isolates ◽  
Gene Cassettes ◽  
Class 1 ◽  
High Level ◽  
Encoding Genes

Molecular detection and surveillance of the resistance genes harboured by Pseudomonas aeruginosa are becoming increasingly important in assessing and controlling spread and colonization in hospitals, and in guiding the treatment of infections. This study analysed the resistance mechanisms of carbapenem-resistant clinical isolates of P. aeruginosa and identified the associated integron-borne metallo-β-lactamase (MBL)-encoding genes. Twenty-seven imipenem (IPM)-resistant clinical isolates of P. aeruginosa were divided into three groups according to their resistance levels to carbapenems. Strains bearing bla IMP-10 showed extremely high-level resistance to IPM, with MICs of 512–2048 μg ml−1. By comparison, strains bearing bla IMP-1, bla IMP-7 and bla VIM-2 showed an intermediate level of resistance, with MICs of 32–256 μg ml−1. The non-MBL-producing strains showed a low level of resistance, with MICs of 8–32 μg ml−1. The same trend in resistance levels was also observed when resistance to other carbapenems, such as meropenem and panipenem, was determined. DNA sequencing showed that the MBL-encoding gene cassettes were carried by class 1 integrons. The bla IMP-1, bla IMP-7 and bla IMP-10 gene cassettes were preceded by a hybrid P ant promoter, TGGACA-N17-TAAACT, and the bla VIM-2 gene cassette was preceded by a weak promoter, TGGACA-N17-TAAGCT. Most of the MBL-encoding genes were linked to one or two resistance genes encoding aminoglycoside-modifying enzymes, such as aac(6′)Iae, aac(6′)II, aacA7, aacC4, aadA1, aadA2 and aadA6, highlighting the multidrug-resistant properties of these clinical isolates.

scholarly journals On the emergence, spread and resistance of Candida auris: host, pathogen and environmental tipping points

2021 ◽  
Vol 70 (3) ◽  
Author(s):  
Arunaloke Chakrabarti ◽  
Prashant Sood
Keyword(s):  
Multidrug Resistant ◽  
Resistance Mechanisms ◽  
Effective Management ◽  
Genetic Determinants ◽  
Candida Auris ◽  
Global Spread ◽  
Host Pathogen ◽  
Invasive Infections ◽  
High Level ◽  
Level Resistance

Over a decade ago, a multidrug-resistant nosocomial fungus Candida auris emerged worldwide and has since become a significant challenge for clinicians and microbiologists across the globe. A resilient pathogen, C. auris survives harsh disinfectants, desiccation and high-saline environments. It readily colonizes the inanimate environment, susceptible patients and causes invasive infections that exact a high toll. Prone to misidentification by conventional microbiology techniques, C. auris rapidly acquires multiple genetic determinants that confer multidrug resistance. Whole-genome sequencing has identified four distinct clades of C. auris, and possibly a fifth one, in circulation. Even as our understanding of this formidable pathogen grows, the nearly simultaneous emergence of its distinct clades in different parts of the world, followed by their rapid global spread, remains largely unexplained. We contend that certain host–pathogen–environmental factors have been evolving along adverse trajectories for the last few decades, especially in regions where C. auris originally appeared, until these factors possibly reached a tipping point to compel the evolution, emergence and spread of C. auris. Comparative genomics has helped identify several resistance mechanisms in C. auris that are analogous to those seen in other Candida species, but they fail to fully explain how high-level resistance rapidly develops in this yeast. A better understanding of these unresolved aspects is essential not only for the effective management of C. auris patients, hospital outbreaks and its global spread but also for forecasting and tackling novel resistant pathogens that might emerge in the future. In this review, we discuss the emergence, spread and resistance of C. auris, and propose future investigations to tackle this resilient pathogen.

scholarly journals Substitutions in SurA and BamA Lead to Reduced Susceptibility to Broad Range Antibiotics in Gonococci

Genes ◽  
2021 ◽  
Vol 12 (9) ◽  
pp. 1312
Author(s):  
Ivan Bodoev ◽  
Maja Malakhova ◽  
Julia Bespyatykh ◽  
Dmitry Bespiatykh ◽  
Georgij Arapidi ◽  
...  
Keyword(s):  
Clinical Isolate ◽  
Efflux Pump ◽  
Cell Envelope ◽  
Multidrug Resistant ◽  
Resistance Mechanisms ◽  
Antibiotic Resistant ◽  
Efflux Pump Inhibition ◽  
Periplasmic Chaperone ◽  
Quantitative Changes ◽  
Periplasmic Chaperones

There is growing concern about the emergence and spread of multidrug-resistant Neisseria gonorrhoeae. To effectively control antibiotic-resistant bacterial pathogens, it is necessary to develop new antimicrobials and to understand the resistance mechanisms to existing antibiotics. In this study, we discovered the unexpected onset of drug resistance in N. gonorrhoeae caused by amino acid substitutions in the periplasmic chaperone SurA and the β-barrel assembly machinery component BamA. Here, we investigated the i19.05 clinical isolate with mutations in corresponding genes along with reduced susceptibility to penicillin, tetracycline, and azithromycin. The mutant strain NG05 (surAmut bamAmut, and penAmut) was obtained using the pan-susceptible n01.08 clinical isolate as a recipient in the transformation procedure. Comparative proteomic analysis of NG05 and n01.08 strains revealed significantly increased levels of other chaperones, Skp and FkpA, and some transport proteins. Efflux pump inhibition experiments demonstrated that the reduction in sensitivity was achieved due to the activity of efflux pumps. We hypothesize that the described mutations in the surA and bamA genes cause the qualitative and quantitative changes of periplasmic chaperones, which in turn alters the function of synthesized cell envelope proteins.

scholarly journals Varied-shaped gold nanoparticles with nanogram killing efficiency as potential antimicrobial surface coatings for the medical devices

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Ewelina Piktel ◽  
Łukasz Suprewicz ◽  
Joanna Depciuch ◽  
Sylwia Chmielewska ◽  
Karol Skłodowski ◽  
...  
Keyword(s):  
Gold Nanoparticles ◽  
Medical Devices ◽  
Multidrug Resistant ◽  
Resistance Mechanisms ◽  
Antimicrobial Spectrum ◽  
Antimicrobial Coatings ◽  
Low Toxicity ◽  
Spherical Gold Nanoparticles ◽  
Cost Efficient ◽  
Bactericidal Efficiency

AbstractMedical device-associated infections are a serious medical threat, particularly for patients with impaired mobility and/or advanced age. Despite a variety of antimicrobial coatings for medical devices being explored to date, only a limited number have been introduced for clinical use. Research into new bactericidal agents with the ability to eradicate pathogens, limit biofilm formation, and exhibit satisfactory biocompatibility, is therefore necessary and urgent. In this study, a series of varied-morphology gold nanoparticles in shapes of rods, peanuts, stars and spherical-like, porous ones with potent antibacterial activity were synthesized and thoroughly tested against spectrum of Candida albicans, Pseudomonas aeruginosa, Staphylococcus aureus clinical strains, as well as spectrum of uropathogenic Escherichia coli isolates. The optimization of gold nanoparticles synthesis allowed to develop nanomaterials, which are proved to be significantly more potent against tested microbes compared with the gold nanoformulations reported to date. Notably, their antimicrobial spectrum includes strains with different drug resistance mechanisms. Facile and cost-efficient synthesis of gold nanoparticles, remarkable bactericidal efficiency at nanogram doses, and low toxicity, underline their potential for development as a new coatings, as indicated by the example of urological catheters. The presented research fills a gap in microbial studies of non-spherical gold nanoparticles for the development of antimicrobial coatings targeting multidrug-resistant pathogens responsible for device-associated nosocomial infections.

scholarly journals 1280. In-Vitro Activity of Cefiderocol, Imipenem/Relebactam, & Ceftazidime/Avibactam in Ceftolozane/Tazobactam Resistant Strains of Multidrug Resistant Pseudomonas aeruginosa

2020 ◽  
Vol 7 (Supplement_1) ◽  
pp. S655-S655
Author(s):  
Daniel Navas ◽  
Angela Charles ◽  
Amy Carr ◽  
Jose Alexander
Keyword(s):  
Multidrug Resistant ◽  
Resistance Mechanisms ◽  
Vitro Activity ◽  
Clinical Isolates ◽  
Resistance Testing ◽  
Clinical Samples ◽  
In Vitro Activity ◽  
Carbapenemase Gene ◽  
Resistant Strains

Abstract Background The activity of imipenem/relebactam (I/R), ceftazidime/avibactam (CZA) and cefiderocol (FDC) were evaluated against clinical isolates of multidrug resistant (MDR) strains of P. aeruginosa which was resistant to ceftolozane/tazobactam (C/T). The recent increase of MDR P. aeruginosa strains isolated from clinical samples has prompted research and development of new antimicrobials that can withstand its multiple resistance mechanisms. C/T is an effective option for treatment of MDR P. aeruginosa in our facility with only 10% of resistance in MDR strains, but the emergence of resistance may occur due to the presence of a carbapenemase gene or an ampC mutation. Methods Antimicrobial susceptibility testing for C/T Etest® (bioMérieux, Inc.) were performed on all MDR strains initially screened by the VITEK2® (bioMérieux, Inc.). 10% (n=20) of all MDR isolates were resistant to C/T by the CLSI 2019 breakpoints. These resistant isolates were tested for presence of a carbapenemase gene using the GeneXpert CARBA-R (Cepheid®) PCR and against CZA Etest® (bioMérieux, Inc.) I/R gradient strips (Liofilchem®) and FDC broth microdilution (Thermo Scientific™ Sensititre™). Results A total of 20 clinical isolates of MDR P. aeruginosa resistant to C/T were tested following standardized CLSI protocols and techniques. All 20 isolates were screened for the presence of a carbapenemase gene (blaVIM, blaNDM, blaKPC, blaOXA-48, blaIMP). A blaVIM gene was detected in 6 (30%) out of 20 isolates. FDC demonstrated the greatest activity with 85% (n=17) of susceptible isolates (CLSI MIC <4µg/dL). CZA (CLSI MIC <8µg/dL) and I/R (FDA MIC <2µg/dL) showed 15% (n=3) and 10% (n=2) of susceptible isolates respectively. FDC was active against all 6 blaVIM isolates, where all 6 strains were resistant to CZA and I/R as expected. 3 isolates tested non-susceptible against FDC; additional characterization was not performed at this time. Conclusion Based on these results, FDC demonstrated the greatest in-vitro activity against C/T resistant strains of MDR P. aeruginosa. FDC also demonstrated activity against all 6 MDR P. aeruginosa carrying blaVIM gene. FDC is a strong option to consider on MDR P. aeruginosa strains based on a resistance testing algorithm and a cost/effective protocol. Disclosures All Authors: No reported disclosures

scholarly journals Evolutionarily recent dual obligatory symbiosis among adelgids indicates a transition between fungus- and insect-associated lifestyles

2021 ◽  
Author(s):  
Gitta Szabó ◽  
Frederik Schulz ◽  
Alejandro Manzano-Marín ◽  
Elena Rebecca Toenshoff ◽  
Matthias Horn
Keyword(s):  
Defense Mechanisms ◽  
Amino Acid Production ◽  
Evolutionary Transition ◽  
Evolutionary Time ◽  
Evolutionary Trajectories ◽  
Host Infection ◽  
Phylogenomic Analyses ◽  
Time Specific ◽  
High Level ◽  
Metagenomic Approach

AbstractAdelgids (Insecta: Hemiptera: Adelgidae) form a small group of insects but harbor a surprisingly diverse set of bacteriocyte-associated endosymbionts, which suggest multiple replacement and acquisition of symbionts over evolutionary time. Specific pairs of symbionts have been associated with adelgid lineages specialized on different secondary host conifers. Using a metagenomic approach, we investigated the symbiosis of the Adelges laricis/Adelgestardus species complex containing betaproteobacterial (“Candidatus Vallotia tarda”) and gammaproteobacterial (“Candidatus Profftia tarda”) symbionts. Genomic characteristics and metabolic pathway reconstructions revealed that Vallotia and Profftia are evolutionary young endosymbionts, which complement each other’s role in essential amino acid production. Phylogenomic analyses and a high level of genomic synteny indicate an origin of the betaproteobacterial symbiont from endosymbionts of Rhizopus fungi. This evolutionary transition was accompanied with substantial loss of functions related to transcription regulation, secondary metabolite production, bacterial defense mechanisms, host infection, and manipulation. The transition from fungus to insect endosymbionts extends our current framework about evolutionary trajectories of host-associated microbes.

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