scholarly journals Enhanced Staphylolytic Activity of the Staphylococcus aureus Bacteriophage vB_SauS-phiIPLA88 HydH5 Virion-Associated Peptidoglycan Hydrolase: Fusions, Deletions, and Synergy with LysH5

2012 ◽  
Vol 78 (7) ◽  
pp. 2241-2248 ◽  
Author(s):  
Lorena Rodríguez-Rubio ◽  
Beatriz Martínez ◽  
Ana Rodríguez ◽  
David M. Donovan ◽  
Pilar García
Keyword(s):  
Staphylococcus Aureus ◽  
Fusion Proteins ◽  
Antimicrobial Agents ◽  
Lytic Activity ◽  
Peptidoglycan Hydrolase ◽  
Content Type ◽  
Gram Positive Bacteria ◽  
Peptidoglycan Hydrolases ◽  
Antimicrobial Synergy

ABSTRACTVirion-associated peptidoglycan hydrolases have potential as antimicrobial agents due to their ability to lyse Gram-positive bacteria on contact. In this work, our aim was to improve the lytic activity of HydH5, a virion-associated peptidoglycan hydrolase from theStaphylococcus aureusbacteriophage vB_SauS-phiIPLA88. Full-length HydH5 and two truncated derivatives containing only the CHAP (cysteine, histidine-dependent amidohydrolase/peptidase) domain exhibited high lytic activity against liveS. aureuscells. In addition, three different fusion proteins were created between lysostaphin and HydH5, each of which showed higher staphylolytic activity than the parental enzyme or its deletion construct. Both parental and fusion proteins lysedS. aureuscells in zymograms and plate lysis and turbidity reduction assays. In plate lysis assays, HydH5 and its derivative fusions lysed bovine and humanS. aureusstrains, the methicillin-resistantS. aureus(MRSA) strain N315, and humanStaphylococcus epidermidisstrains. Several nonstaphylococcal bacteria were not affected. HydH5 and its derivative fusion proteins displayed antimicrobial synergy with the endolysin LysH5in vitro, suggesting that the two enzymes have distinct cut sites and, thus, may be more efficient in combination for the elimination of staphylococcal infections.

scholarly journals In Vitro Activity of Eravacycline against Gram-Positive Bacteria Isolated in Clinical Laboratories Worldwide from 2013 to 2017

2019 ◽  
Vol 64 (3) ◽  
Author(s):  
Ian Morrissey ◽  
Stephen Hawser ◽  
Sibylle H. Lob ◽  
James A. Karlowsky ◽  
Matteo Bassetti ◽  
...  
Keyword(s):  
Antimicrobial Agents ◽  
Clinical Isolates ◽  
Gram Positive ◽  
Content Type ◽  
Gram Positive Bacteria ◽  
Microdilution Method ◽  
Clinical Laboratories ◽  
Broth Microdilution Method ◽  
Doubling Dilution

ABSTRACT Eravacycline is a novel, fully synthetic fluorocycline antibiotic being developed for the treatment of serious infections, including those caused by resistant Gram-positive pathogens. Here, we evaluated the in vitro activities of eravacycline and comparator antimicrobial agents against a recent global collection of frequently encountered clinical isolates of Gram-positive bacteria. The CLSI broth microdilution method was used to determine in vitro MIC data for isolates of Enterococcus spp. (n = 2,807), Staphylococcus spp. (n = 4,331), and Streptococcus spp. (n = 3,373) isolated primarily from respiratory, intra-abdominal, urinary, and skin specimens by clinical laboratories in 37 countries on three continents from 2013 to 2017. Susceptibilities were interpreted using both CLSI and EUCAST breakpoints. There were no substantive differences (a >1-doubling-dilution increase or decrease) in eravacycline MIC90 values for different species/organism groups over time or by region. Eravacycline showed MIC50 and MIC90 results of 0.06 and 0.12 μg/ml, respectively, when tested against Staphylococcus aureus, regardless of methicillin susceptibility. The MIC90 values of eravacycline for Staphylococcus epidermidis and Staphylococcus haemolyticus were equal (0.5 μg/ml). The eravacycline MIC90s for Enterococcus faecalis and Enterococcus faecium were 0.06 μg/ml and were within 1 doubling dilution regardless of the vancomycin susceptibility profile. Eravacycline exhibited MIC90 results of ≤0.06 μg/ml when tested against Streptococcus pneumoniae and beta-hemolytic and viridans group streptococcal isolates. In this surveillance study, eravacycline demonstrated potent in vitro activity against frequently isolated clinical isolates of Gram-positive bacteria (Enterococcus, Staphylococcus, and Streptococcus spp.), including isolates collected over a 5-year period (2013 to 2017), underscoring its potential benefit in the treatment of infections caused by common Gram-positive pathogens.

scholarly journals In Vitro Activity of Tedizolid Compared to Linezolid and Five Other Antimicrobial Agents against 332 Anaerobic Isolates, Including Bacteroides fragilis Group, Prevotella, Porphyromonas, and Veillonella Species

2020 ◽  
Vol 64 (9) ◽  
Author(s):  
Ellie J. C. Goldstein ◽  
C. Vreni Merriam ◽  
Diane M. Citron
Keyword(s):  
Staphylococcus Aureus ◽  
Antimicrobial Agents ◽  
Bacteroides Fragilis ◽  
Vitro Activity ◽  
Mixed Infections ◽  
In Vitro Activity ◽  
Content Type ◽  
Bacteroides Fragilis Group ◽  
Group Species

ABSTRACT Tedizolid’s anaerobic activity is unappreciated. In this study, it was active against all 332 anaerobic isolates tested at ≤2 μg/ml except Bilophila wadsworthia and was more active than linezolid against Bacteroides fragilis group species (MIC90, 1 μg/ml versus 2 to 4 μg/ml). Tedizolid was active against Gram-positive anaerobes (MIC90 for clostridia, 0.25 to 1 μg/ml; MIC90 for anaerobic cocci, ≤0.06 to 0.25 μg/ml). Our data coupled with clinical reports indicate that clinicians should consider its use in mixed infections where Staphylococcus aureus and anaerobes are involved.

scholarly journals In VitroActivity of Ceftaroline against Staphylococcus aureus Isolated in 2012 from Asia-Pacific Countries as Part of the AWARE Surveillance Program

2015 ◽  
Vol 60 (1) ◽  
pp. 343-347 ◽  
Author(s):  
Douglas J. Biedenbach ◽  
Richard A. Alm ◽  
Sushmita D. Lahiri ◽  
Edina Reiszner ◽  
Daryl J. Hoban ◽  
...  
Keyword(s):  
Staphylococcus Aureus ◽  
Antimicrobial Agents ◽  
Generation Cephalosporin ◽  
Sequence Type ◽  
Asia Pacific ◽  
Surveillance Program ◽  
Ceftaroline Fosamil ◽  
Content Type ◽  
Susceptibility Data

ABSTRACTCeftaroline, the active metabolite of the prodrug ceftaroline-fosamil, is an advanced-generation cephalosporin with activity against methicillin-resistantStaphylococcus aureus(MRSA). This investigation providesin vitrosusceptibility data for ceftaroline against 1,971S. aureusisolates collected in 2012 from seven countries (26 centers) in the Asia-Pacific region as part of the Assessing Worldwide Antimicrobial Resistance and Evaluation (AWARE) program. Broth microdilution as recommended by the CLSI was used to determine susceptibility. In all, 62% of the isolates studied were MRSA, and the ceftaroline MIC90for allS. aureusisolates was 2 μg/ml (interpretive criteria: susceptible, ≤1 μg/ml). The overall ceftaroline susceptibility rate forS. aureuswas 86.9%, with 100% of methicillin-sensitiveS. aureusisolates and 78.8% of MRSA isolates susceptible to this agent. The highest percentages of ceftaroline-nonsusceptible MRSA isolates came from China (47.6%), all of which showed intermediate susceptibility, and Thailand (37.1%), where over half (52.8%) of isolates were resistant to ceftaroline (MIC, 4 μg/ml). Thirty-eight ceftaroline-nonsusceptible isolates (MIC values of 2 to 4 μg/ml) were selected for molecular characterization. Among the isolates analyzed, sequence type 5 (ST-5) was the most common sequence type encountered; however, all isolates analyzed from Thailand were ST-228. Penicillin-binding protein 2a (PBP2a) substitution patterns varied by country, but all isolates from Thailand had the Glu239Lys substitution, and 12 of these also carried an additional Glu447Lys substitution. Ceftaroline-fosamil is a useful addition to the antimicrobial agents that can be used to treatS. aureusinfections. However, with the capability of this species to develop resistance to new agents, it is important to recognize and monitor regional differences in trends as they emerge.

scholarly journals Antistaphylococcal Activity of TD-1792, a Multivalent Glycopeptide-Cephalosporin Antibiotic

2011 ◽  
Vol 56 (3) ◽  
pp. 1584-1587 ◽  
Author(s):  
Johanne Blais ◽  
Stacey R. Lewis ◽  
Kevin M. Krause ◽  
Bret M. Benton
Keyword(s):  
Staphylococcus Aureus ◽  
Multidrug Resistant ◽  
Postantibiotic Effect ◽  
Content Type ◽  
Gram Positive Bacteria ◽  
Highly Active ◽  
Antistaphylococcal Activity ◽  
Cephalosporin Antibiotic ◽  
Time Kill

ABSTRACTTD-1792 is a new multivalent glycopeptide-cephalosporin antibiotic with potent activity against Gram-positive bacteria. Thein vitroactivity of TD-1792 was tested against 527Staphylococcus aureusisolates, including multidrug-resistant isolates. TD-1792 was highly active against methicillin-susceptibleS. aureus(MIC90, 0.015 μg/ml), methicillin-resistantS. aureus, and heterogeneous vancomycin-intermediateS. aureus(MIC90, 0.03 μg/ml). Time-kill studies demonstrated the potent bactericidal activity of TD-1792 at concentrations of ≤0.12 μg/ml. A postantibiotic effect of >2 h was observed after exposure to TD-1792.

scholarly journals Combination of Pantothenamides with Vanin Inhibitors as a Novel Antibiotic Strategy against Gram-Positive Bacteria

2013 ◽  
Vol 57 (10) ◽  
pp. 4794-4800 ◽  
Author(s):  
Patrick A. M. Jansen ◽  
Pedro H. H. Hermkens ◽  
Patrick L. J. M. Zeeuwen ◽  
Peter N. M. Botman ◽  
Richard H. Blaauw ◽  
...  
Keyword(s):  
Antimicrobial Agents ◽  
Acid Synthesis ◽  
Spectrometric Analysis ◽  
Gram Positive ◽  
Content Type ◽  
Gram Positive Bacteria ◽  
New Compounds ◽  
Emergence Of Resistance ◽  
Hydrolysis Of

ABSTRACTThe emergence of resistance against current antibiotics calls for the development of new compounds to treat infectious diseases. Synthetic pantothenamides are pantothenate analogs that possess broad-spectrum antibacterial activityin vitroin minimal media. Pantothenamides were shown to be substrates of the bacterial coenzyme A (CoA) biosynthetic pathway, causing cellular CoA depletion and interference with fatty acid synthesis. In spite of their potential use and selectivity for bacterial metabolic routes, these compounds have never made it to the clinic. In the present study, we show that pantothenamides are not active as antibiotics in the presence of serum, and we found that they were hydrolyzed by ubiquitous pantetheinases of the vanin family. To address this further, we synthesized a series of pantetheinase inhibitors based on a pantothenate scaffold that inhibited serum pantetheinase activity in the nanomolar range. Mass spectrometric analysis showed that addition of these pantetheinase inhibitors prevented hydrolysis of pantothenamides by serum. We found that combinations of these novel pantetheinase inhibitors and prototypic pantothenamides like N5-Pan and N7-Pan exerted antimicrobial activityin vitro, particularly against Gram-positive bacteria (Staphylococcus aureus,Staphylococcus epidermidis,Streptococcus pneumoniae, andStreptococcus pyogenes) even in the presence of serum. These results indicate that pantothenamides, when protected against degradation by host pantetheinases, are potentially useful antimicrobial agents.

scholarly journals Ceftaroline Increases Membrane Binding and Enhances the Activity of Daptomycin against Daptomycin-Nonsusceptible Vancomycin-Intermediate Staphylococcus aureus in a Pharmacokinetic/Pharmacodynamic Model

2012 ◽  
Vol 57 (1) ◽  
pp. 66-73 ◽  
Author(s):  
Brian J. Werth ◽  
George Sakoulas ◽  
Warren E. Rose ◽  
Joseph Pogliano ◽  
Ryan Tewhey ◽  
...  
Keyword(s):  
Staphylococcus Aureus ◽  
Cell Wall ◽  
Wall Thickness ◽  
Antimicrobial Agents ◽  
Single Agent ◽  
Pharmacodynamic Model ◽  
Cell Wall Thickness ◽  
Ceftaroline Fosamil ◽  
Content Type

ABSTRACTNew antimicrobial agents and novel combination therapies are needed to treat serious infections caused by methicillin-resistantStaphylococcus aureus(MRSA) with reduced susceptibility to daptomycin and vancomycin. The purpose of this study was to evaluate the combination of ceftaroline plus daptomycin or vancomycin in anin vitropharmacokinetic/pharmacodynamic model. Simulations of ceftaroline-fosamil at 600 mg per kg of body weight every 8 h (q8h) (maximum free-drug concentration in serum [fCmax], 15.2 mg/liter; half-life [t1/2], 2.3 h), daptomycin at 10 mg/kg/day (fCmax, 11.3 mg/liter;t1/2, 8 h), vancomycin at 2 g q12h (fCmax, 30 mg/liter;t1/2, 6 h), ceftaroline plus daptomycin, and ceftaroline plus vancomycin were evaluated against a clinical, isogenic MRSA strain pair: D592 (daptomycin susceptible and heterogeneous vancomycin intermediate) and D712 (daptomycin nonsusceptible and vancomycin intermediate) in a one-compartmentin vitropharmacokinetic/pharmacodynamic model over 96 h. Therapeutic enhancement of combinations was defined as ≥2 log10CFU/ml reduction over the most active single agent. The effect of ceftaroline on the membrane charge, cell wall thickness, susceptibility to killing by the human cathelicidin LL37, and daptomycin binding were evaluated. Therapeutic enhancement was observed with daptomycin plus ceftaroline in both strains and vancomycin plus ceftaroline against D592. Ceftaroline exposure enhanced daptomycin-induced depolarization (81.7% versus 72.3%;P= 0.03) and killing by cathelicidin LL37 (P< 0.01) and reduced cell wall thickness (P< 0.001). Fluorescence-labeled daptomycin was bound over 7-fold more in ceftaroline-exposed cells. Whole-genome sequencing and mutation analysis of these strains indicated that change in daptomycin susceptibility is related to anfmtC(mprF) mutation. The combination of daptomycin plus ceftaroline appears to be potent, with rapid and sustained bactericidal activity against both daptomycin-susceptible and -nonsusceptible strains of MRSA.

scholarly journals In vitro properties of antimicrobial bromotyrosine alkaloids

2006 ◽  
Vol 55 (4) ◽  
pp. 407-415 ◽  
Author(s):  
Neora Pick ◽  
Mamta Rawat ◽  
Dorit Arad ◽  
Jiong Lan ◽  
Junfa Fan ◽  
...  
Keyword(s):  
Staphylococcus Aureus ◽  
Antimicrobial Agents ◽  
Lead Compound ◽  
Gram Positive ◽  
Gram Positive Bacteria ◽  
Monocytes And Macrophages ◽  
Natural Inhibitor ◽  
Low Toxicity ◽  
Vancomycin Resistant

A bromotyrosine alkaloid family of antimicrobial agents was synthesized using the known structure of a natural inhibitor of the mycobacterial mycothiol S-conjugate amidase (MCA) as a template. This series of compounds represents a novel class of anti-infective agents against Gram-positive pathogens, including mycobacteria and meticillin- and vancomycin-resistant Staphylococcus aureus. The fact that these compounds are active against mycobacterial strains in which the MCA gene is deleted and against Gram-positive bacteria lacking mycothiol suggests the existence of an alternative target for these compounds. One member of this family, EXEG1706, was identified as the lead compound possessing low MICs (2·5–25 μg ml−1) for several clinical isolates, whilst having low toxicity for THP-1 monocytes and macrophages.

scholarly journals Novel Bacteriophage Lysin with Broad Lytic Activity Protects against Mixed Infection by Streptococcus pyogenes and Methicillin-Resistant Staphylococcus aureus

2013 ◽  
Vol 57 (6) ◽  
pp. 2743-2750 ◽  
Author(s):  
Daniel B. Gilmer ◽  
Jonathan E. Schmitz ◽  
Chad W. Euler ◽  
Vincent A. Fischetti
Keyword(s):  
Staphylococcus Aureus ◽  
Streptococcus Pyogenes ◽  
Catalytic Domain ◽  
Group A Streptococcus ◽  
Group B Streptococcus ◽  
Streptococcus Suis ◽  
Lytic Activity ◽  
Methicillin Resistant ◽  
Content Type

ABSTRACTMethicillin-resistantStaphylococcus aureus(MRSA) andStreptococcus pyogenes(group A streptococcus [GrAS]) cause serious and sometimes fatal human diseases. They are among the many Gram-positive pathogens for which resistance to leading antibiotics has emerged. As a result, alternative therapies need to be developed to combat these pathogens. We have identified a novel bacteriophage lysin (PlySs2), derived from aStreptococcus suisphage, with broad lytic activity against MRSA, vancomycin-intermediateS. aureus(VISA),Streptococcus suis,Listeria,Staphylococcus simulans,Staphylococcus epidermidis,Streptococcus equi,Streptococcus agalactiae(group B streptococcus [GBS]),S. pyogenes,Streptococcus sanguinis, group G streptococci (GGS), group E streptococci (GES), andStreptococcus pneumoniae. PlySs2 has an N-terminal cysteine-histidine aminopeptidase (CHAP) catalytic domain and a C-terminal SH3b binding domain. It is stable at 50°C for 30 min, 37°C for >24 h, 4°C for 15 days, and −80°C for >7 months; it maintained full activity after 10 freeze-thaw cycles. PlySs2 at 128 μg/mlin vitroreduced MRSA andS. pyogenesgrowth by 5 logs and 3 logs within 1 h, respectively, and exhibited a MIC of 16 μg/ml for MRSA. A single, 2-mg dose of PlySs2 protected 92% (22/24) of the mice in a bacteremia model of mixed MRSA andS. pyogenesinfection. Serially increasing exposure of MRSA andS. pyogenesto PlySs2 or mupirocin resulted in no observed resistance to PlySs2 and resistance to mupirocin. To date, no other lysin has shown such notable broad lytic activity, stability, and efficacy against multiple, leading, human bacterial pathogens; as such, PlySs2 has all the characteristics to be an effective therapeutic.

scholarly journals Alanine Scanning Mutagenesis of the MEDI4893 (Suvratoxumab) Epitope Reduces Alpha Toxin Lytic Activity In Vitro and Staphylococcus aureus Fitness in Infection Models

2018 ◽  
Vol 62 (11) ◽  
Author(s):  
C. Tkaczyk ◽  
E. Semenova ◽  
Y. Y. Shi ◽  
K. Rosenthal ◽  
V. Oganesyan ◽  
...  
Keyword(s):  
Staphylococcus Aureus ◽  
Pore Formation ◽  
Severe Disease ◽  
Treatment Strategies ◽  
Lytic Activity ◽  
Alpha Toxin ◽  
Alanine Scanning Mutagenesis ◽  
Content Type

ABSTRACT Alpha toxin (AT) is a cytolytic pore-forming toxin that plays a key role in Staphylococcus aureus pathogenesis; consequently, extensive research was undertaken to understand the AT mechanism of action and its utility as a target for novel prophylaxis and treatment strategies against S. aureus infections. MEDI4893 (suvratoxumab) is a human anti-AT IgG1 monoclonal antibody (MAb) that targets AT and is currently in phase 2 clinical development. As shown previously, the MEDI4893-binding epitope on AT is comprised of the highly conserved amino acid regions 177 to 200 and 261 to 271, suggesting these amino acids are important for AT function. To test this hypothesis and gain insight into the effect of mutations in the epitope on AT neutralization by MEDI4893, nine MEDI4893 contact residues in AT were individually mutated to alanine. Consistent with our hypothesis, 8 out of 9 mutants exhibited >2-fold loss in lytic activity resulting from a defect in cell binding and pore formation. MEDI4893 binding affinity was reduced >2-fold (2- to 27-fold) for 7 out of 9 mutants, and no binding was detected for the W187A mutant. MEDI4893 effectively neutralized all of the lytic mutants in vitro and in vivo. When the defective mutants were introduced into an S. aureus clinical isolate, the mutant-expressing strains exhibited less severe disease in mouse models and were effectively neutralized by MEDI4893. These results indicate the MEDI4893 epitope is highly conserved due in part to its role in AT pore formation and bacterial fitness, thereby decreasing the likelihood for the emergence of MAb-resistant variants.

scholarly journals The Tape Measure Protein of the Staphylococcus aureus Bacteriophage vB_SauS-phiIPLA35 Has an Active Muramidase Domain

2012 ◽  
Vol 78 (17) ◽  
pp. 6369-6371 ◽  
Author(s):  
Lorena Rodríguez-Rubio ◽  
Dolores Gutiérrez ◽  
Beatriz Martínez ◽  
Ana Rodríguez ◽  
Friedrich Götz ◽  
...  
Keyword(s):  
Staphylococcus Aureus ◽  
Lytic Activity ◽  
Structural Proteins ◽  
Tape Measure Protein ◽  
Content Type ◽  
Double Stranded Dna ◽  
Tape Measure ◽  
Hydrolytic Activities ◽  
Muramidase Activity

ABSTRACTTailed double-stranded DNA (dsDNA) bacteriophages frequently harbor structural proteins displaying peptidoglycan hydrolytic activities. The tape measure protein fromStaphylococcus aureusbacteriophage vB_SauS-phiIPLA35 has a lysozyme-like and a peptidase_M23 domain. This report shows that the lysozyme-like domain (TG1) has muramidase activity and exhibitsin vitrolytic activity against liveS. aureuscells, an activity that could eventually find use in the treatment of infections.

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