scholarly journals Cationic Antimicrobial Peptide LL-37 Is Effective against both Extra- and Intracellular Staphylococcus aureus

2012 ◽  
Vol 57 (3) ◽  
pp. 1283-1290 ◽  
Author(s):  
Jabeen Noore ◽  
Adly Noore ◽  
Bingyun Li
Keyword(s):  
Staphylococcus Aureus ◽  
Antimicrobial Peptide ◽  
Clinical Strain ◽  
Infection Model ◽  
Intracellular Pathogens ◽  
Recurrent Infections ◽  
Bacterial Killing ◽  
Cationic Antimicrobial Peptide ◽  
Content Type ◽  
Conventional Antibiotics

ABSTRACTThe increasing resistance of bacteria to conventional antibiotics and the challenges posed by intracellular bacteria, which may be responsible for chronic and recurrent infections, have driven the need for advanced antimicrobial drugs for effective elimination of both extra- and intracellular pathogens. The purpose of this study was to determine the killing efficacy of cationic antimicrobial peptide LL-37 compared to conventional antibiotics against extra- and intracellularStaphylococcus aureus. Bacterial killing assays and an infection model of osteoblasts andS. aureuswere studied to determine the bacterial killing efficacy of LL-37 and conventional antibiotics against extra- and intracellularS. aureus. We found that LL-37 was effective in killing extracellularS. aureusat nanomolar concentrations, while lactoferricin B was effective at micromolar concentrations and doxycycline and cefazolin at millimolar concentrations. LL-37 was surprisingly more effective in killing the clinical strain than in killing an ATCC strain ofS. aureus. Moreover, LL-37 was superior to conventional antibiotics in eliminating intracellularS. aureus. The kinetic studies further revealed that LL-37 was fast in eliminating both extra- and intracellularS. aureus. Therefore, LL-37 was shown to be very potent and prompt in eliminating both extra- and intracellularS. aureusand was more effective in killing extra- and intracellularS. aureusthan commonly used conventional antibiotics. LL-37 could potentially be used to treat chronic and recurrent infections due to its effectiveness in eliminating not only extracellular but also intracellular pathogens.

scholarly journals Efficacy of NZ2114, a Novel Plectasin-Derived Cationic Antimicrobial Peptide Antibiotic, in Experimental Endocarditis Due to Methicillin-Resistant Staphylococcus aureus

2011 ◽  
Vol 55 (11) ◽  
pp. 5325-5330 ◽  
Author(s):  
Yan Q. Xiong ◽  
Wessam Abdel Hady ◽  
Antoine Deslandes ◽  
Astrid Rey ◽  
Laurent Fraisse ◽  
...  
Keyword(s):  
Staphylococcus Aureus ◽  
Maximum Effect ◽  
Peptide Antibiotic ◽  
Time Curve ◽  
Cationic Antimicrobial Peptide ◽  
Unbound Fraction ◽  
Methicillin Resistant ◽  
Content Type ◽  
Conventional Antibiotics

ABSTRACTCationic antimicrobial peptides (CAPs) play important roles in host immune defenses. Plectasin is a defensin-like CAP isolated from the saprophytic fungusPseudoplectania nigrella. NZ2114 is a novel variant of plectasin with potent activity against Gram-positive bacteria. In this study, we investigated (i) thein vivopharmacokinetic and pharmacodynamic (PK/PD) characteristics of NZ2114 and (ii) thein vivoefficacy of NZ2114 in comparison with those of two conventional antibiotics, vancomycin or daptomycin, in an experimental rabbit infective endocarditis (IE) model due to a methicillin-resistantStaphylococcus aureus(MRSA) strain (ATCC 33591). All NZ2114 regimens (5, 10, and 20 mg/kg of body weight, intravenously [i.v.], twice daily for 3 days) significantly decreased MRSA densities in cardiac vegetations, kidneys, and spleen versus those in untreated controls, except in one scenario (5 mg/kg, splenic MRSA counts). The efficacy of NZ2114 was clearly dose dependent in all target tissues. At 20 mg/kg, NZ2114 showed a significantly greater efficacy than vancomycin (P< 0.001) and an efficacy similar to that of daptomycin. Of importance, only NZ2114 (in 10- and 20-mg/kg regimens) prevented posttherapy relapse in cardiac vegetations, kidneys, and spleen, while bacterial counts in these target tissues continued to increase in vancomycin- and daptomycin-treated animals. Thesein vivoefficacies were equivalent and significantly correlated with three PK indices investigated:fCmax/MIC (the maximum concentration of the free, unbound fraction of a drug in serum divided by the MIC),fAUC/MIC (where AUC is the area under the concentration-time curve), andf%T>MIC(%T>MICis the cumulative percentage of a 24-h period that the drug concentration exceeds the MIC under steady-state pharmacokinetic conditions), as analyzed by a sigmoid maximum-effect (Emax) model (R2> 0.69). The superior efficacy of NZ2114 in this MRSA IE model suggests the potential for further development of this compound for treating serious MRSA infections.

scholarly journals Serine-Aspartate Repeat Protein D Increases Staphylococcus aureus Virulence and Survival in Blood

2016 ◽  
Vol 85 (1) ◽  
Author(s):  
Fatemeh Askarian ◽  
Satoshi Uchiyama ◽  
J. Andrés Valderrama ◽  
Clement Ajayi ◽  
Johanna U. E. Sollid ◽  
...  
Keyword(s):  
Staphylococcus Aureus ◽  
Ex Vivo ◽  
Innate Immune ◽  
Human Neutrophils ◽  
Infection Model ◽  
Bacterial Survival ◽  
Bacterial Killing ◽  
Content Type ◽  
Repeat Protein

ABSTRACT Staphylococcus aureus expresses a panel of cell wall-anchored adhesins, including proteins belonging to the microbial surface components recognizing adhesive matrix molecule (MSCRAMM) family, exemplified by the serine-aspartate repeat protein D (SdrD), which serve key roles in colonization and infection. Deletion of sdrD from S. aureus subsp. aureus strain NCTC8325-4 attenuated bacterial survival in human whole blood ex vivo, which was associated with increased killing by human neutrophils. Remarkably, SdrD was able to inhibit innate immune-mediated bacterial killing independently of other S. aureus proteins, since addition of recombinant SdrD protein and heterologous expression of SdrD in Lactococcus lactis promoted bacterial survival in human blood. SdrD contributes to bacterial virulence in vivo, since fewer S. aureus subsp. aureus NCTC8325-4 ΔsdrD bacteria than bacteria of the parent strain were recovered from blood and several organs using a murine intravenous infection model. Collectively, our findings reveal a new property of SdrD as an important key contributor to S. aureus survival and the ability to escape the innate immune system in blood.

scholarly journals Sequential Evolution of Vancomycin-Intermediate Resistance Alters Virulence in Staphylococcus aureus: Pharmacokinetic/Pharmacodynamic Targets for Vancomycin Exposure

2015 ◽  
Vol 60 (3) ◽  
pp. 1584-1591 ◽  
Author(s):  
Justin R. Lenhard ◽  
Tanya Brown ◽  
Michael J. Rybak ◽  
Calvin J. Meaney ◽  
Nicholas B. Norgard ◽  
...  
Keyword(s):  
Staphylococcus Aureus ◽  
Galleria Mellonella ◽  
Infection Model ◽  
Bacterial Reduction ◽  
Accessory Gene ◽  
Time Curve ◽  
Bacterial Killing ◽  
Unbound Fraction ◽  
Content Type ◽  
Intermediate Resistance

Staphylococcus aureuspossesses exceptional virulence and a remarkable ability to adapt in the face of antibiotic therapy. We examined thein vitroevolution ofS. aureusin response to escalating vancomycin exposure by evaluating bacterial killing and the progression of resistance. A hollow-fiber infection model was utilized to simulate human doses of vancomycin increasing from 0.5 to 4 g every 12 h (q12h) versus a high inoculum (108CFU/ml) of methicillin-resistantS. aureus(MRSA) USA300 and USA400. Host-pathogen interactions usingGalleria mellonellaand accessory gene regulator (agr) expression were studied in serially obtained isolates. In both USA300 and USA400 MRSA isolates, vancomycin exposure up to 2 g q12h resulted in persistence and regrowth, whereas 4 g administered q12h achieved sustained killing against both strains. As vancomycin exposure increased from 0.5 to 2 g q12h, the bacterial population shifted toward vancomycin-intermediate resistance, and collateral increases in the MICs of daptomycin and televancin were observed over 10 days. Guideline-recommended exposure of a ratio of the area under the concentration-time curve for the free, unbound fraction of the drug to the MIC (fAUC/MIC ratio) of 200 displayed a 0.344-log bacterial reduction in area, whereasfAUC/MICs of 371 and 554 were needed to achieve 1.00- and 2.00-log reductions in area, respectively. The stepwise increase in resistance paralleled a decrease inG. mellonellamortality (P= 0.021) and a gradual decline of RNAIII expression over 10 days. Currently recommended doses of vancomycin resulted in amplification of resistance and collateral damage to other antibiotics. Decreases inagrexpression and virulence during therapy may be an adaptive mechanism ofS. aureuspersistence.

scholarly journals Imcroporin, a New Cationic Antimicrobial Peptide from the Venom of the Scorpion Isometrus maculates

2009 ◽  
Vol 53 (8) ◽  
pp. 3472-3477 ◽  
Author(s):  
Zhenhuan Zhao ◽  
Yibao Ma ◽  
Chao Dai ◽  
Ruiming Zhao ◽  
SongRyong Li ◽  
...  
Keyword(s):  
Staphylococcus Aureus ◽  
Antimicrobial Peptide ◽  
Multidrug Resistant ◽  
New Drugs ◽  
Lead Compound ◽  
Cationic Antimicrobial Peptide ◽  
Antibiotic Resistant ◽  
Multidrug Resistant Pathogens ◽  
Conventional Antibiotics

ABSTRACT The pace of resistance against antibiotics almost exceeds that of the development of new drugs. As many bacteria have become resistant to conventional antibiotics, new drugs or drug resources are badly needed to combat antibiotic-resistant pathogens, like methicillin-resistant Staphylococcus aureus (MRSA). Antimicrobial peptides, rich sources existing in nature, are able to effectively kill multidrug-resistant pathogens. Here, imcroporin, a new antimicrobial peptide, was screened and isolated from the cDNA library of the venomous gland of Isometrus maculates. The MIC of imcroporin against MRSA was 50 μg/ml, 8-fold lower than that of cefotaxime and 40-fold lower than that of penicillin. Imcroporin killed bacteria rapidly in vitro, inhibited bacterial growth, and cured infected mice. These results revealed that imcroporin could be considered a potential anti-infective drug or lead compound, especially for treating antibiotic-resistant pathogens.

scholarly journals Comparative Mechanistic Studies of Brilacidin, Daptomycin, and the Antimicrobial Peptide LL16

2014 ◽  
Vol 58 (9) ◽  
pp. 5136-5145 ◽  
Author(s):  
Bruk Mensa ◽  
Gabriella L. Howell ◽  
Richard Scott ◽  
William F. DeGrado
Keyword(s):  
Staphylococcus Aureus ◽  
Antimicrobial Peptide ◽  
Stress Responses ◽  
Protein Misfolding ◽  
Transcriptional Profiling ◽  
Gram Positive ◽  
Cationic Antimicrobial Peptide ◽  
Content Type ◽  
Component Systems ◽  
Two Component Systems

ABSTRACTBrilacidin (PMX30063) has shown potent bactericidal activity against drug-resistant and -susceptible strains of multiple Gram-negative and Gram-positive pathogens. In this study, we demonstrate that brilacidin causes membrane depolarization in the Gram-positive bacteriumStaphylococcus aureus, to an extent comparable to that caused by the lipopeptidic drug daptomycin. Transcriptional profiling ofStaphylococcus aureusby deep sequencing shows that the global response to brilacidin treatment is well correlated to those of treatment with daptomycin and the cationic antimicrobial peptide LL37 and mostly indicates abrogation of cell wall and membrane functions. Furthermore, the upregulation of various chaperones and proteases by brilacidin and daptomycin indicates that cytoplasmic protein misfolding stress may be a contributor to the mechanism of action of these drugs. These stress responses were orchestrated mainly by three two-component systems, GraSR, VraSR, and NsaSR, which have been implicated in virulence and drug resistance against other clinically available antibiotics.

scholarly journals Front-Loaded Linezolid Regimens Result in Increased Killing and Suppression of the Accessory Gene Regulator System of Staphylococcus aureus

2012 ◽  
Vol 56 (7) ◽  
pp. 3712-3719 ◽  
Author(s):  
Brian T. Tsuji ◽  
Tanya Brown ◽  
Ridhi Parasrampuria ◽  
Daniel A. Brazeau ◽  
Alan Forrest ◽  
...  
Keyword(s):  
Staphylococcus Aureus ◽  
Growth Control ◽  
Study Endpoint ◽  
Infection Model ◽  
Accessory Gene ◽  
Bacterial Killing ◽  
Content Type ◽  
Accessory Gene Regulator ◽  
Pharmacodynamic Profile ◽  
The Impact

ABSTRACTFront loading is a strategy used to optimize the pharmacodynamic profile of an antibiotic through the administration of high doses early in therapy for a short duration. Our aims were to evaluate the impact of front loading of linezolid regimens on bacterial killing and suppression of resistance and on RNAIII, the effector molecule of the accessory gene regulator system (encoded byagr) in methicillin-resistantStaphylococcus aureus(MRSA). Time-killing experiments over 48 h were utilized for linezolid against four strains of MRSA: USA100, USA300, USA400, and ATCC 29213. A hollow-fiber infection model simulated traditional and front-loaded human therapeutic regimens of linezolid versus USA300 at 106CFU/ml over 240 h. Over 48 h in time-kill experiments, linezolid displayed bacteriostatic activity, with reductions of >1 log10CFU/ml for all strains. Front-loaded regimens that were administered over 5 days, 1,200 mg every 12 h (q12h) (total, 10 doses) and 2,400 mg q12h (total, 10 doses) followed by 300 mg q12h thereafter, resulted in sustained bactericidal activity, with reductions of the area under the CFU curve of −6.15 and −6.03, respectively, reaching undetectable limits at the 10-day study endpoint. All regimens displayed a reduction in RNAIII relative expression at 24 h and 240 h compared with that of the growth control. Monte Carlo simulations predicted a <1.27× increase in the fractional decreases in platelets for all front-loaded regimens versus the 600 mg q12h regimen, except for the highest-dose front-loaded regimen. Front-loading strategies for linezolid are promising and may be of utility in severe MRSA infections, where early aggressive therapy is necessary.

scholarly journals Characterization of the Antimicrobial Peptide Penisin, a Class Ia Novel Lantibiotic from Paenibacillus sp. Strain A3

2015 ◽  
Vol 60 (1) ◽  
pp. 580-591 ◽  
Author(s):  
Piyush Baindara ◽  
Vasvi Chaudhry ◽  
Garima Mittal ◽  
Luciano M. Liao ◽  
Carolina O. Matos ◽  
...  
Keyword(s):  
Staphylococcus Aureus ◽  
Antimicrobial Peptide ◽  
Posttranslational Modifications ◽  
Random Coil ◽  
Infection Model ◽  
Entire Genome ◽  
Content Type ◽  
Entire Genome Sequence ◽  
Paenibacillus Sp

ABSTRACTAttempts to isolate novel antimicrobial peptides from microbial sources have been on the rise recently, despite their low efficacy in therapeutic applications. Here, we report identification and characterization of a new efficient antimicrobial peptide from a bacterial strain designated A3 that exhibited highest identity withPaenibacillus ehimensis. Upon purification and subsequent molecular characterization of the antimicrobial peptide, referred to as penisin, we found the peptide to be a bacteriocin-like peptide. Consistent with these results, RAST analysis of the entire genome sequence revealed the presence of a lantibiotic gene cluster containing genes necessary for synthesis and maturation of a lantibiotic. While circular dichroism and one-dimension nuclear magnetic resonance experiments confirmed a random coil structure of the peptide, similar to other known lantibiotics, additional biochemical evidence suggests posttranslational modifications of the core peptide yield six thioether cross-links. The deduced amino acid sequence of the putative biosynthetic genepenAshowed approximately 74% similarity with elgicin A and 50% similarity with the lantibiotic paenicidin A. Penisin effectively killed methicillin-resistantStaphylococcus aureus(MRSA) and did not exhibit hemolysis activity. Unlike other lantibiotics, it effectively inhibited the growth of Gram-negative bacteria. Furthermore, 80 mg/kg of body weight of penisin significantly reduced bacterial burden in a mouse thigh infection model and protected BALB/c mice in a bacteremia model entailing infection withStaphylococcus aureusMTCC 96, suggesting that it could be a promising new antimicrobial peptide.

scholarly journals GraXSR Proteins Interact with the VraFG ABC Transporter To Form a Five-Component System Required for Cationic Antimicrobial Peptide Sensing and Resistance in Staphylococcus aureus

2011 ◽  
Vol 56 (2) ◽  
pp. 1047-1058 ◽  
Author(s):  
Mélanie Falord ◽  
Gouzel Karimova ◽  
Aurélia Hiron ◽  
Tarek Msadek
Keyword(s):  
Staphylococcus Aureus ◽  
Antimicrobial Peptide ◽  
Abc Transporter ◽  
Multicomponent System ◽  
Hybrid Approach ◽  
Cationic Antimicrobial Peptide ◽  
Component System ◽  
Content Type ◽  
Amino Terminal ◽  
Genes Encoding

ABSTRACTThe GraSR two-component system (TCS) controls cationic antimicrobial peptide (CAMP) resistance inStaphylococcus aureusthrough the synthesis of enzymes that increase bacterial cell surface positive charges, byd-alanylation of teichoic acids and lysylination of phosphatidylglycerol, leading to electrostatic repulsion of CAMPs. The GraS histidine kinase belongs to the “intramembrane-sensing kinases” subfamily, with a structure featuring a short amino-terminal sensing domain, and two transmembrane helices separated only by a short loop, thought to be buried in the cytoplasmic membrane. The GraSR TCS is in fact a multicomponent system, requiring at least one accessory protein, GraX, in order to function, which, as we show here, acts by signaling through the GraS kinase. ThegraXRSgenes are located immediately upstream from genes encoding an ABC transporter,vraFG, whose expression is controlled by GraSR. We demonstrated that the VraFG transporter does not act as a detoxification module, as it cannot confer resistance when produced on its own, but instead plays an essential role by sensing the presence of CAMPs and signaling through GraS to activate GraR-dependent transcription. A bacterial two-hybrid approach, designed to identify interactions between the GraXSR and VraFG proteins, was carried out in order to understand how they act in detecting and signaling the presence of CAMPs. We identified many interactions between these protein pairs, notably between the GraS kinase and both GraX and the VraG permease, indicating the existence of an original five-component system involved in CAMP sensing and signal transduction to promoteS. aureusresistance.

scholarly journals Decreased Vancomycin Susceptibility in Staphylococcus aureus Caused by IS256Tempering of WalKR Expression

2013 ◽  
Vol 57 (7) ◽  
pp. 3240-3249 ◽  
Author(s):  
Christopher R. E. McEvoy ◽  
Brian Tsuji ◽  
Wei Gao ◽  
Torsten Seemann ◽  
Jessica L. Porter ◽  
...  
Keyword(s):  
Staphylococcus Aureus ◽  
Fluorescent Protein ◽  
Site Directed Mutagenesis ◽  
Infection Model ◽  
Content Type ◽  
Reverse Transcription Pcr ◽  
Phenotype Analysis ◽  
Dosing Regimens ◽  
Mrsa Strains ◽  
Green Fluorescent

ABSTRACTVancomycin-intermediateStaphylococcus aureus(VISA) strains often arise by mutations in the essential two-component regulatorwalKR; however their impact onwalKRfunction has not been definitively established. Here, we investigated 10 MRSA strains recovered serially after exposure of vancomycin-susceptibleS. aureus(VSSA) JKD6009 to simulated human vancomycin dosing regimens (500 mg to 4,000 mg every 12 h) using a 10-day hollow fiber infection model. After continued exposure to the vancomycin regimens, two isolates displayed reduced susceptibility to both vancomycin and daptomycin, developing independent IS256insertions in thewalKR5′ untranslated region (5′ UTR). Quantitative reverse transcription-PCR (RT-PCR) revealed a 50% reduction inwalKRgene expression in the IS256mutants compared to the VSSA parent. Green fluorescent protein (GFP) reporter analysis, promoter mapping, and site-directed mutagenesis confirmed these findings and showed that the IS256insertions had replaced two SigA-likewalKRpromoters with weaker, hybrid promoters. Removal of IS256reverted the phenotype to VSSA, showing that reduced expression of WalKR did induce the VISA phenotype. Analysis of selected WalKR-regulated autolysins revealed upregulation ofssaAbut no change in expression ofsakandsceDin both IS256mutants. Whole-genome sequencing of the two mutants revealed an additional IS256insertion withinagrCfor one mutant, and we confirmed that this mutation abolishedagrfunction. These data provide the first substantial analysis ofwalKRpromoter function and show that prolonged vancomycin exposure can result in VISA through an IS256-mediated reduction inwalKRexpression; however, the mechanisms by which this occurs remain to be determined.

scholarly journals Activity of Meropenem-Vaborbactam againstPseudomonas aeruginosaandAcinetobacter baumanniiin a Neutropenic Mouse Thigh Infection Model

2018 ◽  
Vol 63 (1) ◽  
Author(s):  
Mojgan Sabet ◽  
Ziad Tarazi ◽  
David C. Griffith
Keyword(s):  
Pseudomonas Aeruginosa ◽  
Acinetobacter Baumannii ◽  
Clinical Isolates ◽  
Infection Model ◽  
Model Data ◽  
Bacterial Killing ◽  
Content Type

ABSTRACTWe have evaluated the activity of meropenem-vaborbactam against clinical isolates ofPseudomonas aeruginosaandAcinetobacter baumanniiin a neutropenic mouse thigh infection model. Data show that meropenem-vaborbactam regimens equivalent to 3-h infusions every 8 h with 2 g meropenem and 2 g vaborbactam produced bacterial killing against strains with MICs of 2 to 16 mg/liter and suggests that this combination may have utility in the treatment of infections caused byP. aeruginosaandA. baumannii.

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