scholarly journals A Phage Lysin Fused to a Cell-Penetrating Peptide Kills Intracellular Methicillin-Resistant Staphylococcus aureus in Keratinocytes and Has Potential as a Treatment for Skin Infections in Mice

2018 ◽  
Vol 84 (12) ◽  
Author(s):  
ZhaoFei Wang ◽  
LiCheng Kong ◽  
Yang Liu ◽  
Qiang Fu ◽  
ZeLin Cui ◽  
...  
Keyword(s):  
Staphylococcus Aureus ◽  
Resistant Bacteria ◽  
Cell Penetrating Peptide ◽  
Skin Infections ◽  
Promising Alternative ◽  
Methicillin Resistant ◽  
Content Type ◽  
Skin Structure ◽  
Cell Penetrating ◽  
A Cell

ABSTRACT Staphylococcus aureus is the main pathogen that causes skin and skin structure infections and is able to survive and persist in keratinocytes of the epidermis. Since the evolution of multidrug-resistant bacteria, the use of phages and their lysins has presented a promising alternative approach to treatment. In this study, a cell wall hydrolase (also called lysin) derived from Staphylococcus phage JD007 (JDlys) was identified. JDlys showed strong lytic activity against methicillin-resistant Staphylococcus aureus (MRSA) strains from different sources and of different multilocus sequence typing (MLST) types. Furthermore, a fusion protein consisting of a cell-penetrating peptide derived from the trans -activating transcription (Tat) factor fused to JDlys (CPP Tat -JDlys) was used to kill MRSA bacteria causing intracellular infections. CPP Tat -JDlys, in which the fusion of CPP Tat to JDlys had almost no effect on the bacteriolytic activity of JDlys, was able to effectively eliminate intracellular MRSA bacteria and alleviate the inflammatory response and cell damage caused by MRSA. Specifically, CPP Tat -JDlys was able to combat MRSA-induced murine skin infections and, consequently, expedite the healing of cutaneous abscesses. These data suggest that the novel antimicrobial CPP-JDlys may be a worthwhile candidate as a treatment for skin and skin structure infections caused by MRSA. IMPORTANCE S. aureus is the main cause of skin and skin structure infections due to its ability to invade and survive in the epithelial barrier. Due to the overuse of antibiotics in humans and animals, S. aureus has shown a high capacity for acquiring and accumulating mechanisms of resistance to antibiotics. Moreover, most antibiotics are usually limited in their ability to overcome the intracellular persistence of bacteria causing skin and skin structure infections. So, it is critical to seek a novel antimicrobial agent to eradicate intracellular S. aureus . In this study, a cell-penetrating peptide fused to lysin (CPP-JDlys) was engineered. Our results show that CPP-JDlys can enter keratinocytes and effectively eliminate intracellular MRSA. Meanwhile, experiments with mice revealed that CPP-JDlys efficiently inhibits the proliferation of MRSA in murine skin and thus shortens the course of wound healing. Our results indicate that the CPP-fused lysin has potential for use for the treatment of skin infections caused by MRSA.

scholarly journals Synthesis, Characterization and Estimation the Biological Activity of New Mesomorphic Heterocyclic Compounds

2020 ◽  
Vol 10 (01) ◽  
pp. 106-113
Author(s):  
Hussain A. Hamza ◽  
Nasreen R. Jber
Keyword(s):  
Staphylococcus Aureus ◽  
Antibiotic Resistance ◽  
Methicillin Resistant Staphylococcus Aureus ◽  
High Titer ◽  
Resistant Bacteria ◽  
Skin Infections ◽  
Promising Alternative ◽  
Methicillin Resistant ◽  
Phage Cocktail

Methicillin-resistant Staphylococcus aureus (MRSA) is a S. aureus that resistant to β-lactam antibiotics (e.g., Cefoxitin and Oxacillin). MRSA has a tremendous capacity to develop resistance to other classes of antibiotics and forming a real threat to patients. The process of exploring a new tactic of non-antibiotic treatments has become an urgent need. A bacteriophage is one of the possible treatments that strongly suggested. Bacteriophages are viruses that infect bacteria as a natural host with a bactericidal capability against multidrug-resistant bacteria that do not respond to conventional antibiotics. The current study investigates the lytic efficacy of phage-cocktail in vitro, specifically against S. aureus isolated from skin infections and find out the possible association of phage-antibiotic resistance. A total of 43 isolates of Methicillin-resistant staphylococcus aureus were isolated from skin infections. The isolates are distributed as (10 isolates of burn, 4 isolates of diabetic foot ulcer, 7 isolates of surgical wounds, 3 isolates of pressure ulcer, and 19 of skin and soft tissue infection). The isolates exhibited variant antibiotic susceptibility against 12 antibiotics (Cefoxitin FOX, Vancomycin VAN, Oxacillin OX, Rifampin RA, Chloramphenicol C, Nitrofurantoin F, Clindamycin DA, Azithromycin AZM, Amikacin AK, Trimethoprim-sulfamethoxazole SXT, Ciprofloxacin CIP, and Gentamicin CN). A bacteriophage cocktail was isolated using a phage-enrichment technique, high titer phage lysate (5*109 pfu/ml) was obtained and investigated against 43 MRSA isolates. The phage-cocktail showed high specificity to S. aureus but variable susceptibility to 43 MRSA isolates. It was observed that there was no association (p greater than 0.05) between phage and antibiotic resistance of (FOX, OX, VAN, RA, C, F, and DA) where the significant association was observed (p less than 0.05) with (AZM, AK, SXT, CIP, and CN). Significantly, the more antibiotic-resistant isolates exhibited more sensitivity to phage-cocktail, which represents a promising alternative to antibiotics that do not affect with increasing antibiotic resistance.

scholarly journals ComparativeIn VitroActivities of Oritavancin, Dalbavancin, and Vancomycin against Methicillin-Resistant Staphylococcus aureus Isolates in a Nondividing State

2016 ◽  
Vol 60 (7) ◽  
pp. 4342-4345 ◽  
Author(s):  
Adam Belley ◽  
David Lalonde Seguin ◽  
Francis Arhin ◽  
Greg Moeck
Keyword(s):  
Staphylococcus Aureus ◽  
Bactericidal Activity ◽  
Antibacterial Agents ◽  
Methicillin Resistant Staphylococcus Aureus ◽  
Methicillin Resistant ◽  
Content Type ◽  
Skin Structure ◽  
Persistent Infections ◽  
Time Kill

ABSTRACTAntibacterial agents that kill nondividing bacteria may be of utility in treating persistent infections. Oritavancin and dalbavancin are bactericidal lipoglycopeptides that are approved for acute bacterial skin and skin structure infections in adults caused by susceptible Gram-positive pathogens. Using time-kill methodology, we demonstrate that oritavancin exerts bactericidal activity against methicillin-resistantStaphylococcus aureus(MRSA) isolates that are maintained in a nondividing statein vitro, whereas dalbavancin and the glycopeptide vancomycin do not.

scholarly journals Prospective Investigation of Nasal Mupirocin, Hexachlorophene Body Wash, and Systemic Antibiotics for Prevention of Recurrent Community-Associated Methicillin-Resistant Staphylococcus aureus Infections

2011 ◽  
Vol 56 (2) ◽  
pp. 1084-1086 ◽  
Author(s):  
Loren G. Miller ◽  
Jennifer Tan ◽  
Samantha J. Eells ◽  
Esther Benitez ◽  
Allen B. Radner
Keyword(s):  
Staphylococcus Aureus ◽  
Methicillin Resistant Staphylococcus Aureus ◽  
Skin Infections ◽  
Methicillin Resistant ◽  
Content Type ◽  
Nasal Mupirocin ◽  
The Mean ◽  
Systemic Antibiotics ◽  
Prospective Investigation

ABSTRACTRecurrent community-associated methicillin-resistantStaphylococcus aureus(CA-MRSA) skin infections are an increasingly common problem. However, there are no data on the efficacy of decolonization regimens. We prospectively evaluated 31 patients with recurrent CA-MRSA skin infections who received nasal mupirocin, topical hexachlorophene body wash, and an oral anti-MRSA antibiotic. The mean number of MRSA infections after the intervention decreased significantly from baseline (0.03 versus 0.84 infections/month,P= <0.0001). This regimen appears promising at preventing recurrent CA-MRSA infections.

scholarly journals Innate Immune Memory Contributes to Host Defense against Recurrent Skin and Skin Structure Infections Caused by Methicillin-Resistant Staphylococcus aureus

2016 ◽  
Vol 85 (2) ◽  
Author(s):  
Liana C. Chan ◽  
Siyang Chaili ◽  
Scott G. Filler ◽  
Lloyd S. Miller ◽  
Norma V. Solis ◽  
...  
Keyword(s):  
Staphylococcus Aureus ◽  
Host Defense ◽  
Protective Efficacy ◽  
Innate Immune ◽  
Immune Memory ◽  
Wild Type ◽  
Methicillin Resistant ◽  
Content Type ◽  
Skin Structure ◽  
Mrsa Infection

ABSTRACT Staphylococcus aureus is the leading cause of skin and skin structure infections (SSSI). The high frequency of recurring SSSI due to S. aureus, including methicillin-resistant S. aureus (MRSA) strains, despite high titers of specific antibodies and circulating T cells, implies that traditional adaptive immunity imparts incomplete protection. We hypothesized that innate immune memory contributes to the protective host defense against recurring MRSA infection. To test this hypothesis, SSSI was induced in wild-type and rag1 −/− mice in the BALB/c and C57BL/6 backgrounds. Prior infection (priming) of wild-type and rag1 −/− mice of either background afforded protection against repeat infection, as evidenced by reduced abscess severities and decreased CFU densities compared to those in naive controls. Interestingly, protection was greater on the previously infected flank than on the naive flank for wild-type and rag1 −/− mice. For wild-type mice, protective efficacy corresponded to increased infiltration of neutrophils (polymorphonuclear leukocytes [PMN]), macrophages (MΦ), Langerin+ dendritic cells (LDC), and natural killer (NK) cells. Protection was associated with the induction of interleukin-17A (IL-17A), IL-22, and gamma interferon (IFN-γ) as well as the antimicrobial peptides CRAMP and mβD-3. Priming also protected rag1 −/− mice against recurring SSSI, with increased MΦ and LDC infiltration and induction of IL-22, CRAMP, and mβD-3. These findings suggest that innate immune memory, mediated by specific cellular and molecular programs, likely contributes to the localized host defense in recurrent MRSA SSSI. These insights support the development of targeted immunotherapeutic strategies to address the challenge of MRSA infection.

scholarly journals Identification of Pyruvate Kinase in Methicillin-Resistant Staphylococcus aureus as a Novel Antimicrobial Drug Target

2011 ◽  
Vol 55 (5) ◽  
pp. 2042-2053 ◽  
Author(s):  
Roya Zoraghi ◽  
Raymond H. See ◽  
Peter Axerio-Cilies ◽  
Nag S. Kumar ◽  
Huansheng Gong ◽  
...  
Keyword(s):  
Staphylococcus Aureus ◽  
Pyruvate Kinase ◽  
Drug Target ◽  
Multidrug Resistant ◽  
Resistant Bacteria ◽  
Antibacterial Drug ◽  
Methicillin Resistant ◽  
Content Type ◽  
Antistaphylococcal Activity

ABSTRACTNovel classes of antimicrobials are needed to address the challenge of multidrug-resistant bacteria such as methicillin-resistantStaphylococcus aureus(MRSA). Using the architecture of the MRSA interactome, we identified pyruvate kinase (PK) as a potential novel drug target based upon it being a highly connected, essential hub in the MRSA interactome. Structural modeling, including X-ray crystallography, revealed discrete features of PK in MRSA, which appeared suitable for the selective targeting of the bacterial enzyme.In silicolibrary screening combined with functional enzymatic assays identified an acyl hydrazone-based compound (IS-130) as a potent MRSA PK inhibitor (50% inhibitory concentration [IC50] of 0.1 μM) with >1,000-fold selectivity over human PK isoforms. Medicinal chemistry around the IS-130 scaffold identified analogs that more potently and selectively inhibited MRSA PK enzymatic activity andS. aureusgrowthin vitro(MIC of 1 to 5 μg/ml). These novel anti-PK compounds were found to possess antistaphylococcal activity, including both MRSA and multidrug-resistantS. aureus(MDRSA) strains. These compounds also exhibited exceptional antibacterial activities against other Gram-positive genera, including enterococci and streptococci. PK lead compounds were found to be noncompetitive inhibitors and were bactericidal. In addition, mutants with significant increases in MICs were not isolated after 25 bacterial passages in culture, indicating that resistance may be slow to emerge. These findings validate the principles of network science as a powerful approach to identify novel antibacterial drug targets. They also provide a proof of principle, based upon PK in MRSA, for a research platform aimed at discovering and optimizing selective inhibitors of novel bacterial targets where human orthologs exist, as leads for anti-infective drug development.

scholarly journals Pharmacodynamics of a Simulated Single 1,200-Milligram Dose of Oritavancin in anIn VitroPharmacokinetic/Pharmacodynamic Model of Methicillin-Resistant Staphylococcus aureus Infection

2012 ◽  
Vol 57 (1) ◽  
pp. 205-211 ◽  
Author(s):  
Adam Belley ◽  
Francis F. Arhin ◽  
Ingrid Sarmiento ◽  
Hong Deng ◽  
Warren Rose ◽  
...  
Keyword(s):  
Staphylococcus Aureus ◽  
Antibacterial Effect ◽  
Pharmacodynamic Model ◽  
Once Daily ◽  
Methicillin Resistant ◽  
Content Type ◽  
Skin Structure ◽  
Mrsa Strains ◽  
Kill Curve

ABSTRACTThe safety and efficacy of a single 1,200-mg dose of the lipoglycopeptide oritavancin are currently being investigated in two global phase 3 studies of acute bacterial skin and skin structure infections. In this study, anin vitropharmacokinetic/pharmacodynamic model was established to compare the free-drug pharmacodynamics associated with a single 1,200-mg dose of oritavancin to once-daily dosing with daptomycin at 6 mg/kg of body weight and twice-daily dosing with vancomycin at 1,000 mg against three methicillin-resistantStaphylococcus aureus(MRSA) strains over 72 h. The area under the bacterial-kill curve (AUBKC) was used to assess the antibacterial effect of each dosing regimen at 24 h (AUBKC0-24), 48 h (AUBKC0-48), and 72 h (AUBKC0-72). The rapid bactericidal activities of oritavancin and daptomycin contributed to lower AUBKC0-24s for the three MRSA strains than with vancomycin (P< 0.05, as determined by analysis of variance [ANOVA]). Oritavancin exposure also resulted in a lower AUBKC0-48and AUBKC0-72against one MRSA strain and a lower AUBKC0-48for another strain than did vancomycin exposure (P< 0.05). Furthermore, daptomycin exposure resulted in a lower AUBKC0-48and AUBKC0-72for one of the MRSA isolates than did vancomycin exposure (P< 0.05). Lower AUBKC0-24s for two of the MRSA strains (P< 0.05) were obtained with oritavancin exposure than with daptomycin. Thus, the antibacterial effect from the single-dose regimen of oritavancin is as effective as that from either once-daily dosing with daptomycin or twice-daily dosing with vancomycin against the MRSA isolates tested in anin vitropharmacokinetic/pharmacodynamic model over 72 h. These results provide further justification to assess the single 1,200-mg dose of oritavancin for treatment of acute bacterial skin and skin structure infections.

scholarly journals Occurrence of Livestock-Associated Methicillin-Resistant Staphylococcus aureus in Turkey and Broiler Barns and Contamination of Air and Soil Surfaces in Their Vicinity

2013 ◽  
Vol 79 (8) ◽  
pp. 2759-2766 ◽  
Author(s):  
A. Friese ◽  
J. Schulz ◽  
K. Zimmermann ◽  
B.-A. Tenhagen ◽  
A. Fetsch ◽  
...  
Keyword(s):  
Staphylococcus Aureus ◽  
Longitudinal Study ◽  
Ambient Air ◽  
Cross Sectional Study ◽  
Resistant Bacteria ◽  
Sectional Study ◽  
Cross Sectional ◽  
Methicillin Resistant ◽  
Content Type ◽  
Poultry Farms

ABSTRACTThe emission of microorganisms, especially resistant bacteria such as methicillin-resistantStaphylococcus aureus(MRSA), from poultry farms is of public interest, and its occurrence and relevance are controversially discussed. So far, there are limited data on this issue. In this study, we investigated the occurrence of livestock-associated (LA)-MRSA inside and outside previously tested MRSA-positive poultry barns in Germany. In total, five turkey and two broiler fattening farms were investigated four and three times, respectively. In a longitudinal study during one fattening period, samples were collected from animals, the animals' environment inside the barn, including the air, and the barns' surroundings, such as ambient air and boot swabs of ground surfaces at different distances from the barn. Moreover, a cross-sectional study was carried out once inside the barns on five turkey and four broiler farms during the last third of the fatting period. In the cross-sectional study, LA-MRSA was detected in the air of most barns (7 of 9, 77.8%), as well as in many samples originating from animals, with detections levels of 50 to 54% in broiler and 62 to 77% in turkey farms. In the longitudinal study, LA-MRSA was found in the ambient air outside two turkey barns and on the ground surface on the downwind side of many (44.4%) turkey and broiler farms. The samespatypes of isolates were observed inside and outside the barns. Transmission of MRSA within poultry farms, as well as emission via the airborne route, seems to be possible.

scholarly journals Mutations inmmpLand in the Cell Wall Stress Stimulon Contribute to Resistance to Oxadiazole Antibiotics in Methicillin-Resistant Staphylococcus aureus

2014 ◽  
Vol 58 (10) ◽  
pp. 5841-5847 ◽  
Author(s):  
Qiaobin Xiao ◽  
Sergei Vakulenko ◽  
Mayland Chang ◽  
Shahriar Mobashery
Keyword(s):  
Staphylococcus Aureus ◽  
Cell Wall ◽  
Wall Stress ◽  
Methicillin Resistant ◽  
Content Type ◽  
Cell Wall Stress ◽  
A Cell ◽  
Putative Member

ABSTRACTStaphylococcus aureusis a leading cause of hospital- and community-acquired infections, which exhibit broad resistance to various antibiotics. We recently disclosed the discovery of the oxadiazole class of antibiotics, which hasin vitroandin vivoactivities against methicillin-resistantS. aureus(MRSA). We report herein that MmpL, a putative member of the resistance, nodulation, and cell division (RND) family of proteins, contributes to oxadiazole resistance in theS. aureusstrain COL. Through serial passages, we generated twoS. aureusCOL variants that showed diminished susceptibilities to an oxadiazole antibiotic. The MICs for the oxadiazole against one strain (designatedS. aureusCOLI) increased reproducibly 2-fold (to 4 μg/ml), while against the other strain (S. aureusCOLR), they increased >4-fold (to >8 μg/ml, the limit of solubility). The COLRstrain was derived from the COLIstrain. Whole-genome sequencing revealed 31 mutations inS. aureusCOLR, of which 29 were shared with COLI. Consistent with our previous finding that oxadiazole antibiotics inhibit cell wall biosynthesis, we found 13 mutations that occurred either in structural genes or in promoters of the genes of the cell wall stress stimulon. Two unique mutations inS. aureusCOLRwere substitutions in two genes that encode the putative thioredoxin (SACOL1794) and MmpL (SACOL2566). A role formmpLin resistance to oxadiazoles was discerned from gene deletion and complementation experiments. To our knowledge, this is the first report that a cell wall-acting antibiotic selects for mutations in the cell wall stress stimulon and the first to implicate MmpL in resistance to antibiotics inS. aureus.

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