scholarly journals Redox Balance via Lactate Dehydrogenase Is Important for Multiple Stress Resistance and Virulence in Enterococcus faecalis

2013 ◽  
Vol 81 (8) ◽  
pp. 2662-2668 ◽  
Author(s):  
Nosheen Fatima Rana ◽  
Nicolas Sauvageot ◽  
Jean-Marie Laplace ◽  
YinYin Bao ◽  
Ingolf Nes ◽  
...  
Keyword(s):  
Lactate Dehydrogenase ◽  
Enterococcus Faecalis ◽  
Drug Target ◽  
Systemic Infection ◽  
Opportunistic Pathogen ◽  
Redox Balance ◽  
Resistant Bacteria ◽  
Antibiotic Resistant ◽  
Content Type ◽  
Hostile Environments

ABSTRACTEnterococcus faecalisis a highly stress resistant opportunistic pathogen. The intrinsic ruggedness of this bacterium is supposed to be the basis of its capacity to colonize the hostile environments of hospitals and to cause several kinds of infections. We show in this work that general resistance to very different environmental stresses depends on the ability ofE. faecalisto maintain redox balance via lactate dehydrogenase (LDH). Furthermore, LDH-deficient mutants are less successful than the wild type at colonizing host organs in a murine model of systemic infection. Taken together, our results, as well as those previously published forStaphylococcus aureus(A. R. Richardson, S. J. Libby, and F. C. Fang, Science 319:1672–1676, 2008), identify LDH as an attractive drug target. These drugs may have additional applications, as in the fight against glycopeptide antibiotic-resistant bacteria and even cancer.

scholarly journals Multiple Roles for Enterococcus faecalis Glycosyltransferases in Biofilm-Associated Antibiotic Resistance, Cell Envelope Integrity, and Conjugative Transfer

2015 ◽  
Vol 59 (7) ◽  
pp. 4094-4105 ◽  
Author(s):  
Jennifer L. Dale ◽  
Julian Cagnazzo ◽  
Chi Q. Phan ◽  
Aaron M. T. Barnes ◽  
Gary M. Dunny
Keyword(s):  
Antibiotic Resistance ◽  
Enterococcus Faecalis ◽  
Cell Envelope ◽  
Opportunistic Pathogen ◽  
Growth Conditions ◽  
Multidrug Resistant ◽  
Resistant Bacteria ◽  
Conjugative Transfer ◽  
Content Type ◽  
Resistance Determinants

ABSTRACTThe emergence of multidrug-resistant bacteria and the limited availability of new antibiotics are of increasing clinical concern. A compounding factor is the ability of microorganisms to form biofilms (communities of cells encased in a protective extracellular matrix) that are intrinsically resistant to antibiotics.Enterococcus faecalisis an opportunistic pathogen that readily forms biofilms and also has the propensity to acquire resistance determinants via horizontal gene transfer. There is intense interest in the genetic basis for intrinsic and acquired antibiotic resistance inE. faecalis, since clinical isolates exhibiting resistance to multiple antibiotics are not uncommon. We performed a genetic screen using a library of transposon (Tn) mutants to identifyE. faecalisbiofilm-associated antibiotic resistance determinants. Five Tn mutants formed wild-type biofilms in the absence of antibiotics but produced decreased biofilm biomass in the presence of antibiotic concentrations that were subinhibitory to the parent strain. Genetic determinants responsible for biofilm-associated antibiotic resistance include components of the quorum-sensing system (fsrA,fsrC, andgelE) and two glycosyltransferase (GTF) genes (epaIandepaOX). We also found that the GTFs play additional roles inE. faecalisresistance to detergent and bile salts, maintenance of cell envelope integrity, determination of cell shape, polysaccharide composition, and conjugative transfer of the pheromone-inducible plasmid pCF10. TheepaOXgene is located in a variable extended region of the enterococcal polysaccharide antigen (epa) locus. These data illustrate the importance of GTFs inE. faecalisadaptation to diverse growth conditions and suggest new targets for antimicrobial design.

scholarly journals Gastrointestinal Dissemination and Transmission of Staphylococcus aureus following Bacteremia

2014 ◽  
Vol 83 (1) ◽  
pp. 372-378 ◽  
Author(s):  
Elisabeth Kernbauer ◽  
Katie Maurer ◽  
Victor J. Torres ◽  
Bo Shopsin ◽  
Ken Cadwell
Keyword(s):  
Staphylococcus Aureus ◽  
Systemic Infection ◽  
Experimental System ◽  
Resistant Bacteria ◽  
Antibiotic Resistant ◽  
Content Type ◽  
Component Systems ◽  
Single Host ◽  
Two Component Systems ◽  
Selection For

Mutations that alter virulence and antibiotic susceptibility arise and persist duringStaphylococcus aureusbacteremia. However, an experimental system demonstrating transmission following bacteremia has been lacking, and thus implications of within-host adaptation for between-host transmission are unknown. We report thatS. aureusdisseminates to the gastrointestinal tract of mice following intravenous injection and readily transmits to cohoused naive mice. Both intestinal dissemination and transmission were linked to the production of virulence factors based on gene deletion studies of thesaeandagrtwo-component systems. Furthermore, antimicrobial selection for antibiotic-resistantS. aureusdisplaced susceptibleS. aureusfrom the intestine of infected hosts, which led to the preferential transmission and dominance of antibiotic-resistant bacteria among cohoused untreated mice. These findings establish an animal model to investigate gastrointestinal dissemination and transmission ofS. aureusand suggest that adaptation during the course of systemic infection has implications beyond the level of a single host.

scholarly journals Draft Genome Sequence of Antibiotic-Resistant Enterococcus faecalis Strain UMB0843, Isolated from the Female Urinary Tract

2020 ◽  
Vol 9 (20) ◽  
Author(s):  
Natalia Purta ◽  
Taylor Miller-Ensminger ◽  
Adelina Voukadinova ◽  
Alan J. Wolfe ◽  
Catherine Putonti
Keyword(s):  
Antibiotic Resistance ◽  
Urinary Tract ◽  
Enterococcus Faecalis ◽  
Genome Analysis ◽  
Nosocomial Infections ◽  
Draft Genome ◽  
Antibiotic Resistant ◽  
Content Type ◽  
Female Urinary Tract ◽  
Multiple Antibiotics

Here, we introduce the 2.8-Mbp draft genome of Enterococcus faecalis strain UMB0843, isolated from the female urinary tract. E. faecalis is a leading cause of nosocomial infections, and many strains are often resistant to multiple antibiotics. We focus our genome analysis on the multiple genes involved in antibiotic resistance in this strain.

scholarly journals Identification of Novel Bacteriophages with Therapeutic Potential That TargetEnterococcus faecalis

2019 ◽  
Vol 87 (11) ◽  
Author(s):  
M. Al-Zubidi ◽  
M. Widziolek ◽  
E. K. Court ◽  
A. F. Gains ◽  
R. E. Smith ◽  
...  
Keyword(s):  
Host Range ◽  
Root Canal ◽  
Therapeutic Potential ◽  
Opportunistic Pathogen ◽  
Cross Sectional ◽  
Antibiotic Resistant ◽  
Content Type ◽  
Endodontic Infection ◽  
Tail Protein

ABSTRACTThe Gram-positive opportunistic pathogenEnterococcus faecalisis frequently responsible for nosocomial infections in humans and represents one of the most common bacteria isolated from recalcitrant endodontic (root canal) infections.E. faecalisis intrinsically resistant to several antibiotics routinely used in clinical settings (such as cephalosporins and aminoglycosides) and can acquire resistance to vancomycin (vancomycin-resistant enterococci). The resistance ofE. faecalisto several classes of antibiotics and its capacity to form biofilms cause serious therapeutic problems. Here, we report the isolation of several bacteriophages that targetE. faecalisstrains isolated from the oral cavity of patients suffering root canal infections. All phages isolated wereSiphoviridaewith similar tail lengths (200 to 250 nm) and icosahedral heads. The genome sequences of three isolated phages were highly conserved with the exception of predicted tail protein genes that diverge in sequence, potentially reflecting the host range. The properties of the phage with the broadest host range (SHEF2) were further characterized. We show that this phage requires interaction with components of the major and variant region enterococcal polysaccharide antigen to engage in lytic infection. Finally, we explored the therapeutic potential of this phage and show that it can eradicateE. faecalisbiofilms formedin vitroon a standard polystyrene surface but also on a cross-sectional tooth slice model of endodontic infection. We also show that SHEF2 cleared a lethal infection of zebrafish when applied in the circulation. We therefore propose that the phage described here could be used to treat a broad range of antibiotic-resistantE. faecalisinfections.

scholarly journals Fighting Antibiotic-Resistant Klebsiella pneumoniae with “Sweet” Immune Targets

mBio ◽  
2018 ◽  
Vol 9 (3) ◽  
Author(s):  
Roberto Adamo ◽  
Immaculada Margarit
Keyword(s):  
Klebsiella Pneumoniae ◽  
Multidrug Resistant ◽  
Resistant Bacteria ◽  
Therapeutic Approaches ◽  
Antibiotic Resistant ◽  
Content Type ◽  
Carbapenem Resistant ◽  
Surface Polysaccharides ◽  
Resistant Strains ◽  
Murine Monoclonal Antibodies

ABSTRACT Antibiotics and vaccines have greatly impacted human health in the last century by dramatically reducing the morbidity and mortality associated with infectious diseases. The recent challenge posed by the emergence of multidrug-resistant bacteria could possibly be addressed by novel immune prophylactic and therapeutic approaches. Among the newly threatening pathogens, Klebsiella pneumoniae is particularly worrisome in the nosocomial setting, and its surface polysaccharides are regarded as promising antigen candidates. The majority of Klebsiella carbapenem-resistant strains belong to the sequence type 158 (ST258) lineage, with two main clades expressing capsular polysaccharides CPS1 and CPS2. In a recent article, S. D. Kobayashi and colleagues (mBio 9:e00297-18, 2018, https://doi.org/10.1128/mBio.00297-18) show that CPS2-specific IgGs render ST258 clade 2 bacteria more sensitive to human serum and phagocytic killing. E. Diago-Navarro et al. (mBio 9:e00091-18, 2018, https://doi.org/10.1128/mBio.00091-18) generated two murine monoclonal antibodies recognizing distinct glycotopes of CPS2 that presented functional activity against multiple ST258 strains. These complementary studies represent a step toward the control of this dangerous pathogen.

scholarly journals HAMLET, a Protein Complex from Human Milk, Has Bactericidal Activity and Enhances the Activity of Antibiotics against Pathogenic Streptococci

2019 ◽  
Vol 63 (12) ◽  
Author(s):  
Feiruz Alamiri ◽  
Kristian Riesbeck ◽  
Anders P. Hakansson
Keyword(s):  
Human Milk ◽  
Bactericidal Activity ◽  
Combination Treatment ◽  
Bacterial Species ◽  
Penicillin G ◽  
Resistant Bacteria ◽  
Tumoricidal Activity ◽  
Antibiotic Resistant ◽  
Content Type ◽  
Transport Inhibitors

ABSTRACT HAMLET (human alpha-lactalbumin made lethal to tumor cells) is a protein-lipid complex derived from human milk that was first described for its tumoricidal activity. Later studies showed that HAMLET also has direct bactericidal activity against select species of bacteria, with highest activity against Streptococcus pneumoniae. Additionally, HAMLET in combination with various antimicrobial agents can make a broad range of antibiotic-resistant bacterial species sensitive to antibiotics. Here, we show that HAMLET has direct antibacterial activity not only against pneumococci but also against Streptococcus pyogenes (group A streptococci [GAS]) and Streptococcus agalactiae (group B streptococci [GBS]). As with pneumococci, HAMLET treatment of GAS and GBS resulted in depolarization of the bacterial membrane, followed by membrane permeabilization and death, which was able to be inhibited by calcium and sodium transport inhibitors. Treatment of clinical antibiotic-resistant isolates of S. pneumoniae, GAS, and GBS with sublethal concentrations of HAMLET in combination with antibiotics decreased the MICs of the antibiotics into the sensitive range. This effect could also be blocked by ion transport inhibitors, suggesting that HAMLET’s bactericidal and combination treatment effects used similar mechanisms. Finally, we show that HAMLET potentiated the effects of erythromycin against erythromycin-resistant bacteria more effectively than penicillin G potentiated killing bacteria resistant to erythromycin. These results show that HAMLET effectively (i) kills three different species of pathogenic streptococci by similar mechanisms and also (ii) potentiates the activities of macrolides and lincosamides more effectively than combination treatment with beta-lactams. These findings suggest a potential therapeutic role for HAMLET in repurposing antibiotics currently causing treatment failures in patients.

scholarly journals Novel Carbapenemases FLC-1 and IMI-2 Encoded by an Enterobacter cloacae Complex Isolated from Food Products

2019 ◽  
Vol 63 (6) ◽  
Author(s):  
Michael S. M. Brouwer ◽  
Kamaleddin H. M. E. Tehrani ◽  
Michel Rapallini ◽  
Yvon Geurts ◽  
Arie Kant ◽  
...  
Keyword(s):  
General Population ◽  
Enterobacter Cloacae ◽  
Hydrolytic Activity ◽  
Resistant Bacteria ◽  
Human Consumption ◽  
The Novel ◽  
Antibiotic Resistant ◽  
Content Type ◽  
Class A ◽  
Enterobacter Cloacae Complex

ABSTRACT Food for human consumption is screened widely for the presence of antibiotic-resistant bacteria to assess the potential for transfer of resistant bacteria to the general population. Here, we describe an Enterobacter cloacae complex isolated from imported seafood that encodes two carbapenemases on two distinct plasmids. Both enzymes belong to Ambler class A β-lactamases, the previously described IMI-2 and a novel family designated FLC-1. The hydrolytic activity of the novel enzyme against aminopenicillins, cephalosporins, and carbapenems was determined.

scholarly journals Lactate Dehydrogenase Is the Key Enzyme for Pneumococcal Pyruvate Metabolism and Pneumococcal Survival in Blood

2014 ◽  
Vol 82 (12) ◽  
pp. 5099-5109 ◽  
Author(s):  
Paula Gaspar ◽  
Firas A. Y. Al-Bayati ◽  
Peter W. Andrew ◽  
Ana Rute Neves ◽  
Hasan Yesilkaya
Keyword(s):  
Lactate Dehydrogenase ◽  
Lactate Production ◽  
Virulence Gene ◽  
Redox Balance ◽  
Central Metabolism ◽  
Content Type ◽  
Virulence Gene Expression ◽  
Key Enzyme

ABSTRACTStreptococcus pneumoniaeis a fermentative microorganism and causes serious diseases in humans, including otitis media, bacteremia, meningitis, and pneumonia. However, the mechanisms enabling pneumococcal survival in the host and causing disease in different tissues are incompletely understood. The available evidence indicates a strong link between the central metabolism and pneumococcal virulence. To further our knowledge on pneumococcal virulence, we investigated the role of lactate dehydrogenase (LDH), which converts pyruvate to lactate and is an essential enzyme for redox balance, in the pneumococcal central metabolism and virulence using an isogenicldhmutant. Loss of LDH led to a dramatic reduction of the growth rate, pinpointing the key role of this enzyme in fermentative metabolism. The pattern of end products was altered, and lactate production was totally blocked. The fermentation profile was confirmed byin vivonuclear magnetic resonance (NMR) measurements of glucose metabolism in nongrowing cell suspensions of theldhmutant. In this strain, a bottleneck in the fermentative steps is evident from the accumulation of pyruvate, revealing LDH as the most efficient enzyme in pyruvate conversion. An increase in ethanol production was also observed, indicating that in the absence of LDH the redox balance is maintained through alcohol dehydrogenase activity. We also found that the absence of LDH renders the pneumococci avirulent after intravenous infection and leads to a significant reduction in virulence in a model of pneumonia that develops after intranasal infection, likely due to a decrease in energy generation and virulence gene expression.

scholarly journals β-Lactams and Florfenicol Antibiotics Remain Bioactive in Soils while Ciprofloxacin, Neomycin, and Tetracycline Are Neutralized

2011 ◽  
Vol 77 (20) ◽  
pp. 7255-7260 ◽  
Author(s):  
Murugan Subbiah ◽  
Shannon M. Mitchell ◽  
Jeffrey L. Ullman ◽  
Douglas R. Call
Keyword(s):  
High Performance ◽  
Selective Pressure ◽  
Luria Bertani ◽  
Resistant Bacteria ◽  
Antibiotic Resistant ◽  
Content Type ◽  
Adsorption Mechanisms ◽  
E Coli ◽  
Luria Bertani Broth ◽  
Contamination Levels

ABSTRACTIt is generally assumed that antibiotic residues in soils select for antibiotic-resistant bacteria. This assumption was tested by separately adding 10 different antibiotics (≥200 ppm) to three soil-water slurries (silt-loam, sand-loam, and sand; 20% soil [wt/vol]) and incubating mixtures for 24 h at room temperature. The antibiotic activity of the resultant supernatant was assessed by culturing a sensitiveEscherichia colistrain in the filter-sterilized supernatant augmented with Luria-Bertani broth. We found striking differences in the abilities of supernatants to suppress growth of the indicatorE. coli. Ampicillin, cephalothin, cefoxitin, ceftiofur, and florfenicol supernatants completely inhibited growth while bacterial growth was uninhibited in the presence of neomycin, tetracycline, and ciprofloxacin supernatants. High-performance liquid chromatography (HPLC) analysis demonstrated that cefoxitin and florfenicol were almost completely retained in the supernatants, whereas tetracycline and ciprofloxacin were mostly removed. Antibiotic dissipation in soil, presumably dominated by adsorption mechanisms, was sufficient to neutralize 200 ppm of tetracycline; this concentration is considerably higher than reported contamination levels. Soil pellets from the tetracycline slurries were resuspended in a minimal volume of medium to maximize the interaction between bacteria and soil particles, but sensitive bacteria were still unaffected by tetracycline (P= 0.6). Thus, residual antibiotics in soil do not necessarily exert a selective pressure, and the degree to which the pharmaceutical remains bioactive depends on the antibiotic. Efforts to control antibiotic contamination would be better directed toward compounds that retain biological activity in soils (e.g., cephalosporins and florfenicol) because these are the antibiotics that could exert a selective pressure in the environment.

scholarly journals Auranofin exerts broad-spectrum bactericidal activities by targeting thiol-redox homeostasis

2015 ◽  
Vol 112 (14) ◽  
pp. 4453-4458 ◽  
Author(s):  
Michael B. Harbut ◽  
Catherine Vilchèze ◽  
Xiaozhou Luo ◽  
Mary E. Hensler ◽  
Hui Guo ◽  
...  
Keyword(s):  
Redox Homeostasis ◽  
Thioredoxin Reductase ◽  
Redox Balance ◽  
Resistant Bacteria ◽  
Gram Positive ◽  
Antibiotic Resistant ◽  
Gram Positive Bacteria ◽  
Bactericidal Activities ◽  
Orally Bioavailable ◽  
Thiol Redox

Infections caused by antibiotic-resistant bacteria are a rising public health threat and make the identification of new antibiotics a priority. From a cell-based screen for bactericidal compounds againstMycobacterium tuberculosisunder nutrient-deprivation conditions we identified auranofin, an orally bioavailable FDA-approved antirheumatic drug, as having potent bactericidal activities against both replicating and nonreplicatingM. tuberculosis. We also found that auranofin is active against other Gram-positive bacteria, includingBacillus subtilisandEnterococcus faecalis, and drug-sensitive and drug-resistant strains ofEnterococcus faeciumandStaphylococcus aureus. Our biochemical studies showed that auranofin inhibits the bacterial thioredoxin reductase, a protein essential in many Gram-positive bacteria for maintaining the thiol-redox balance and protecting against reactive oxidative species. Auranofin decreases the reducing capacity of target bacteria, thereby sensitizing them to oxidative stress. Finally, auranofin was efficacious in a murine model of methicillin-resistantS. aureusinfection. These results suggest that the thioredoxin-mediated redox cascade of Gram-positive pathogens is a valid target for the development of antibacterial drugs, and that the existing clinical agent auranofin may be repurposed to aid in the treatment of several important antibiotic-resistant pathogens.

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