scholarly journals Assembly of Complete Genome Sequences of Negative-Control and Experimental Strain Variants of Staphylococcus aureus ATCC BAA-39 Selected under the Effect of the Drug FS-1, Which Induces Antibiotic Resistance Reversion

2019 ◽  
Vol 8 (30) ◽  
Author(s):  
Monique Joubert ◽  
Oleg N. Reva ◽  
Ilya S. Korotetskiy ◽  
Sergey V. Shvidko ◽  
Sergey V. Shilov ◽  
...  
Keyword(s):  
Staphylococcus Aureus ◽  
Variant Calling ◽  
Study Drug ◽  
Multidrug Resistant ◽  
Negative Control ◽  
Pacbio Sequencing ◽  
Drug Induced ◽  
Content Type ◽  
Experimental Strain ◽  
And Control

Staphylococcus aureus ATCC BAA-39 is the reference organism for a multidrug-resistant Staphylococcus aureus (MRSA) strain that was used to study drug-induced resistance reversion by an iodine-containing nanomolecular complex, FS-1. PacBio sequencing was performed on both the experimental and control strains, followed by genome assembly, variant calling, and DNA modification profiling.

scholarly journals Activity of Debio1452, a FabI Inhibitor with Potent Activity against Staphylococcus aureus and Coagulase-Negative Staphylococcus spp., Including Multidrug-Resistant Strains

2015 ◽  
Vol 59 (5) ◽  
pp. 2583-2587 ◽  
Author(s):  
Robert K. Flamm ◽  
Paul R. Rhomberg ◽  
Nachum Kaplan ◽  
Ronald N. Jones ◽  
David J. Farrell
Keyword(s):  
Staphylococcus Aureus ◽  
Antimicrobial Agents ◽  
Fatty Acid Biosynthesis ◽  
Multidrug Resistant ◽  
Coagulase Negative Staphylococcus ◽  
Significant Activity ◽  
Coagulase Negative Staphylococci ◽  
Content Type ◽  
Mrsa Strains ◽  
Human Infections

ABSTRACTStaphylococcus aureusand coagulase-negative staphylococci (CoNS) are responsible for a wide variety of human infections. The investigational antibacterial Debio1450 (previously AFN-1720), a prodrug of Debio1452 (previously AFN-1252), specifically targets staphylococci without significant activity against other Gram-positive or Gram-negative species. Debio1452 inhibits FabI, an enzyme critical to fatty acid biosynthesis in staphylococci. The activity of Debio1452 against CoNS, methicillin-susceptibleS. aureus(MSSA), and methicillin-resistantS. aureus(MRSA), including significant clones, was determined. A globally diverse collection of 574 patient isolates from 35 countries was tested that included CoNS (6 species, 103 strains), MSSA (154 strains), MRSA (163 strains), and molecularly characterized strains (includingspa-typed MRSA clones; 154 strains). The isolates were tested for susceptibility by CLSI broth microdilution methods against Debio1452 and 10 comparators. The susceptibility rates for the comparators were determined using CLSI and EUCAST breakpoint criteria. AllS. aureusand CoNS strains were inhibited by Debio1452 concentrations of ≤0.12 and ≤0.5 μg/ml, respectively. The MIC50s for MSSA, MRSA, and molecularly characterized MRSA strains were 0.004 μg/ml, and the MIC90s ranged from 0.008 to 0.03 μg/ml. The MICs were higher for the CoNS isolates (MIC50/90, 0.015/0.12 μg/ml). AmongS. aureusstrains, resistance was common for erythromycin (61.6%), levofloxacin (49.0%), clindamycin (27.6%), tetracycline (15.7%), and trimethoprim-sulfamethoxazole (7.0%). Debio1452 demonstrated potent activity against MSSA, MRSA, and CoNS. Debio1452 showed significantly greater activity overall (MIC50, 0.004 μg/ml) than the other agents tested against these staphylococcal species, which included dominant MRSA clones and strains resistant to currently utilized antimicrobial agents.

scholarly journals Clearance of Staphylococcus aureus from In Vivo Models of Chronic Infection by Immunization Requires Both Planktonic and Biofilm Antigens

2019 ◽  
Vol 88 (1) ◽  
Author(s):  
Janette M. Harro ◽  
Yvonne Achermann ◽  
Jeffrey A. Freiberg ◽  
Devon L. Allison ◽  
Kristen J. Brao ◽  
...  
Keyword(s):  
Staphylococcus Aureus ◽  
Protective Efficacy ◽  
Passive Immunization ◽  
Quadrivalent Vaccine ◽  
Bacterial Populations ◽  
In Vivo Models ◽  
Content Type ◽  
Pentavalent Vaccine ◽  
And Control

ABSTRACT Staphylococcus aureus is a causative agent of chronic biofilm-associated infections that are recalcitrant to resolution by the immune system or antibiotics. To combat these infections, an antistaphylococcal, biofilm-specific quadrivalent vaccine against an osteomyelitis model in rabbits has previously been developed and shown to be effective at eliminating biofilm-embedded bacterial populations. However, the addition of antibiotics was required to eradicate remaining planktonic populations. In this study, a planktonic upregulated antigen was combined with the quadrivalent vaccine to remove the need for antibiotic therapy. Immunization with this pentavalent vaccine followed by intraperitoneal challenge of BALB/c mice with S. aureus resulted in 16.7% and 91.7% mortality in pentavalent vaccine and control groups, respectively (P < 0.001). Complete bacterial elimination was found in 66.7% of the pentavalent cohort, while only 8.3% of the control animals cleared the infection (P < 0.05). Further protective efficacy was observed in immunized rabbits following intramedullary challenge with S. aureus, where 62.5% of the pentavalent cohort completely cleared the infection, versus none of the control animals (P < 0.05). Passive immunization of BALB/c mice with serum IgG against the vaccine antigens prior to intraperitoneal challenge with S. aureus prevented mortality in 100% of mice and eliminated bacteria in 33.3% of the challenged mice. These results demonstrate that targeting both the planktonic and biofilm stages with the pentavalent vaccine or the IgG elicited by immunization can effectively protect against S. aureus infection.

scholarly journals A Small Membrane Stabilizing Protein Critical to the Pathogenicity of Staphylococcus aureus

2020 ◽  
Vol 88 (9) ◽  
Author(s):  
Seána Duggan ◽  
Maisem Laabei ◽  
Alaa Abdulaziz Alnahari ◽  
Eóin C. O’Brien ◽  
Keenan A. Lacey ◽  
...  
Keyword(s):  
Staphylococcus Aureus ◽  
Iron Homeostasis ◽  
Control Strategies ◽  
Antibiotic Resistant ◽  
Content Type ◽  
Promising Target ◽  
Significant Impairment ◽  
The Stability ◽  
Conventional Antibiotics ◽  
And Control

ABSTRACT Staphylococcus aureus is a major human pathogen, and the emergence of antibiotic-resistant strains is making all types of S. aureus infections more challenging to treat. With a pressing need to develop alternative control strategies to use alongside or in place of conventional antibiotics, one approach is the targeting of established virulence factors. However, attempts at this have had little success to date, suggesting that we need to better understand how this pathogen causes disease if effective targets are to be identified. To address this, using a functional genomics approach, we have identified a small membrane-bound protein that we have called MspA. Inactivation of this protein results in the loss of the ability of S. aureus to secrete cytolytic toxins, protect itself from several aspects of the human innate immune system, and control its iron homeostasis. These changes appear to be mediated through a change in the stability of the bacterial membrane as a consequence of iron toxicity. These pleiotropic effects on the ability of the pathogen to interact with its host result in significant impairment in the ability of S. aureus to cause infection in both a subcutaneous and sepsis model of infection. Given the scale of the effect the inactivation of MspA causes, it represents a unique and promising target for the development of a novel therapeutic approach.

scholarly journals Engineering of Long-Circulating Peptidoglycan Hydrolases Enables Efficient Treatment of Systemic Staphylococcus aureus Infection

mBio ◽  
2020 ◽  
Vol 11 (5) ◽  
Author(s):  
Anna M. Sobieraj ◽  
Markus Huemer ◽  
Léa V. Zinsli ◽  
Susanne Meile ◽  
Anja P. Keller ◽  
...  
Keyword(s):  
Staphylococcus Aureus ◽  
Human Blood ◽  
Half Life ◽  
Multidrug Resistant ◽  
Life Extension ◽  
Drug Resistant ◽  
Content Type ◽  
Peptidoglycan Hydrolases ◽  
Life Threatening

ABSTRACT Staphylococcus aureus is a human pathogen causing life-threatening diseases. The increasing prevalence of multidrug-resistant S. aureus infections is a global health concern, requiring development of novel therapeutic options. Peptidoglycan-degrading enzymes (peptidoglycan hydrolases, PGHs) have emerged as a highly effective class of antimicrobial proteins against S. aureus and other pathogens. When applied to Gram-positive bacteria, PGHs hydrolyze bonds within the peptidoglycan layer, leading to rapid bacterial death by lysis. This activity is highly specific and independent of the metabolic activity of the cell or its antibiotic resistance patterns. However, systemic application of PGHs is limited by their often low activity in vivo and by an insufficient serum circulation half-life. To address this problem, we aimed to extend the half-life of PGHs selected for high activity against S. aureus in human serum. Half-life extension and increased serum circulation were achieved through fusion of PGHs to an albumin-binding domain (ABD), resulting in high-affinity recruitment of human serum albumin and formation of large protein complexes. Importantly, the ABD-fused PGHs maintained high killing activity against multiple drug-resistant S. aureus strains, as determined by ex vivo testing in human blood. The top candidate, termed ABD_M23, was tested in vivo to treat S. aureus-induced murine bacteremia. Our findings demonstrate a significantly higher efficacy of ABD_M23 than of the parental M23 enzyme. We conclude that fusion with ABD represents a powerful approach for half-life extension of PGHs, expanding the therapeutic potential of these enzybiotics for treatment of multidrug-resistant bacterial infections. IMPORTANCE Life-threatening infections with Staphylococcus aureus are often difficult to treat due to the increasing prevalence of antibiotic-resistant bacteria and their ability to persist in protected niches in the body. Bacteriolytic enzymes are promising new antimicrobials because they rapidly kill bacteria, including drug-resistant and persisting cells, by destroying their cell wall. However, when injected into the bloodstream, these enzymes are not retained long enough to clear an infection. Here, we describe a modification to increase blood circulation time of the enzymes and enhance treatment efficacy against S. aureus-induced bloodstream infections. This was achieved by preselecting enzyme candidates for high activity in human blood and coupling them to serum albumin, thereby preventing their elimination by kidney filtration and blood vessel cells.

scholarly journals The Ancestral N-Terminal Domain of Big Defensins Drives Bacterially Triggered Assembly into Antimicrobial Nanonets

mBio ◽  
2019 ◽  
Vol 10 (5) ◽  
Author(s):  
Karine Loth ◽  
Agnès Vergnes ◽  
Cairé Barreto ◽  
Sébastien N. Voisin ◽  
Hervé Meudal ◽  
...  
Keyword(s):  
Staphylococcus Aureus ◽  
Antimicrobial Activity ◽  
Bactericidal Activity ◽  
Multidrug Resistant ◽  
High Salt ◽  
Clinical Isolates ◽  
Host Defense Peptides ◽  
Hydrophobic Domain ◽  
Content Type ◽  
Terminal Domain

ABSTRACT Big defensins, ancestors of β-defensins, are composed of a β-defensin-like C-terminal domain and a globular hydrophobic ancestral N-terminal domain. This unique structure is found in a limited number of phylogenetically distant species, including mollusks, ancestral chelicerates, and early-branching cephalochordates, mostly living in marine environments. One puzzling evolutionary issue concerns the advantage for these species of having maintained a hydrophobic domain lost during evolution toward β-defensins. Using native ligation chemistry, we produced the oyster Crassostrea gigas BigDef1 (Cg-BigDef1) and its separate domains. Cg-BigDef1 showed salt-stable and broad-range bactericidal activity, including against multidrug-resistant human clinical isolates of Staphylococcus aureus. We found that the ancestral N-terminal domain confers salt-stable antimicrobial activity to the β-defensin-like domain, which is otherwise inactive. Moreover, upon contact with bacteria, the N-terminal domain drives Cg-BigDef1 assembly into nanonets that entrap and kill bacteria. We speculate that the hydrophobic N-terminal domain of big defensins has been retained in marine phyla to confer salt-stable interactions with bacterial membranes in environments where electrostatic interactions are impaired. Those remarkable properties open the way to future drug developments when physiological salt concentrations inhibit the antimicrobial activity of vertebrate β-defensins. IMPORTANCE β-Defensins are host defense peptides controlling infections in species ranging from humans to invertebrates. However, the antimicrobial activity of most human β-defensins is impaired at physiological salt concentrations. We explored the properties of big defensins, the β-defensin ancestors, which have been conserved in a number of marine organisms, mainly mollusks. By focusing on a big defensin from oyster (Cg-BigDef1), we showed that the N-terminal domain lost during evolution toward β-defensins confers bactericidal activity to Cg-BigDef1, even at high salt concentrations. Cg-BigDef1 killed multidrug-resistant human clinical isolates of Staphylococcus aureus. Moreover, the ancestral N-terminal domain drove the assembly of the big defensin into nanonets in which bacteria are entrapped and killed. This discovery may explain why the ancestral N-terminal domain has been maintained in diverse marine phyla and creates a new path of discovery to design β-defensin derivatives active at physiological and high salt concentrations.

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 Topical Antibiotic Use Coselects for the Carriage of Mobile Genetic Elements Conferring Resistance to Unrelated Antimicrobials in Staphylococcus aureus

2017 ◽  
Vol 62 (2) ◽  
Author(s):  
Glen P. Carter ◽  
Mark B. Schultz ◽  
Sarah L. Baines ◽  
Anders Gonçalves da Silva ◽  
Helen Heffernan ◽  
...  
Keyword(s):  
Staphylococcus Aureus ◽  
New Zealand ◽  
Single Molecule ◽  
Antibiotic Use ◽  
Multidrug Resistant ◽  
Topical Antibiotic ◽  
Content Type ◽  
Topical Antibiotics ◽  
The Impact

ABSTRACTTopical antibiotics, such as mupirocin and fusidic acid, are commonly used in the prevention and treatment of skin infections, particularly those caused by staphylococci. However, the widespread use of these agents is associated with increased resistance to these agents, potentially limiting their efficacy. Of particular concern is the observation that resistance to topical antibiotics is often associated with multidrug resistance, suggesting that topical antibiotics may play a role in the emergence of multidrug-resistant (MDR) strains. New Zealand (NZ) has some of the highest globally recorded rates of topical antibiotic usage and resistance. Using a combination of Pacific Biosciences single-molecule real-time (SMRT) whole-genome sequencing, Illumina short-read sequencing, and Bayesian phylogenomic modeling on 118 new multilocus sequence type 1 (ST1) communityStaphylococcus aureusisolates from New Zealand and 61 publically available international ST1 genome sequences, we demonstrate a strong correlation between the clinical introduction of topical antibiotics and the emergence of MDR ST1S. aureus. We also providein vitroexperimental evidence showing that exposure to topical antibiotics can lead to the rapid selection of MDRS. aureusisolates carrying plasmids that confer resistance to multiple unrelated antibiotics, from within a mixed population of competitor strains. These findings have important implications regarding the impact of the indiscriminate use of topical antibiotics.

scholarly journals Targeting Methicillin-Resistant Staphylococcus aureus with Short Salt-Resistant Synthetic Peptides

2014 ◽  
Vol 58 (7) ◽  
pp. 4113-4122 ◽  
Author(s):  
Mohamed F. Mohamed ◽  
Maha I. Hamed ◽  
Alyssa Panitch ◽  
Mohamed N. Seleem
Keyword(s):  
Staphylococcus Aureus ◽  
Synthetic Peptides ◽  
Bactericidal Effect ◽  
Multidrug Resistant ◽  
Antimicrobial Activities ◽  
Net Charge ◽  
Methicillin Resistant ◽  
Content Type ◽  
C Terminus ◽  
Conventional Antibiotics

ABSTRACTThe seriousness of microbial resistance combined with the lack of new antimicrobials has increased interest in the development of antimicrobial peptides (AMPs) as novel therapeutics. In this study, we evaluated the antimicrobial activities of two short synthetic peptides, namely, RRIKA and RR. These peptides exhibited potent antimicrobial activity againstStaphylococcus aureus, and their antimicrobial effects were significantly enhanced by addition of three amino acids in the C terminus, which consequently increased the amphipathicity, hydrophobicity, and net charge. Moreover, RRIKA and RR demonstrated a significant and rapid bactericidal effect against clinical and drug-resistantStaphylococcusisolates, including methicillin-resistantStaphylococcus aureus(MRSA), vancomycin-intermediateS. aureus(VISA), vancomycin-resistantS. aureus(VRSA), linezolid-resistantS. aureus, and methicillin-resistantStaphylococcus epidermidis. In contrast to many natural AMPs, RRIKA and RR retained their activity in the presence of physiological concentrations of NaCl and MgCl2. Both RRIKA and RR enhanced the killing of lysostaphin more than 1,000-fold and eradicated MRSA and VRSA isolates within 20 min. Furthermore, the peptides presented were superior in reducing adherent biofilms ofS. aureusandS. epidermidiscompared to results with conventional antibiotics. Our findings indicate that the staphylocidal effects of our peptides were through permeabilization of the bacterial membrane, leading to leakage of cytoplasmic contents and cell death. Furthermore, peptides were not toxic to HeLa cells at 4- to 8-fold their antimicrobial concentrations. The potent and salt-insensitive antimicrobial activities of these peptides present an attractive therapeutic candidate for treatment of multidrug-resistantS. aureusinfections.

Multidrug-resistant pathogens isolated from ready-to-eat salads available at a local market in Pakistan

2016 ◽  
Vol 118 (8) ◽  
pp. 2068-2075 ◽  
Author(s):  
Sana Ilyas ◽  
Muhammad Usman Qamar ◽  
Muhammad Hidayat Rasool ◽  
Nazia Abdulhaq ◽  
Zeeshan Nawaz
Keyword(s):  
Staphylococcus Aureus ◽  
Clavulanic Acid ◽  
Antimicrobial Susceptibility ◽  
National Level ◽  
Multidrug Resistant ◽  
Effective Control ◽  
Local Market ◽  
Content Type ◽  
Amoxicillin Clavulanic Acid ◽  
Multidrug Resistant Pathogens

Purpose – The purpose of this paper is to evaluate the frequency and antimicrobial susceptibility pattern of pathogens present in ready-to-eat salads available at a local market. Design/methodology/approach – A 100 salad samples were collected aseptically. Each sample (25 g) was homogenized in 225 ml of sterile peptone water and was serially diluted up to 1×106. Dilutions were inoculated on nutrient agar by surface spread plate technique. Aerobic colony count (ACC) was estimated by counting the colonies. Bacterial isolates were cultured on blood and MacConkey agar and identified on the basis of their morphology, culture characteristics and confirmed by API 20E and 20NE. Antimicrobial susceptibility was determined as per CLSI 2014. Findings – ACC range was 1.1×103 cfu/g to 5.8×109 cfu/g. Among these the highest ACC was found in channa chat (4.9×104 to 5.8×109 cfu/g). A total of 127 microorganisms were identified; 73 were gram negative rods (GNRs) and 24 were gram positive cocci (GPC). Among GNRs; Klebsiella spp. (n=18) was the predominant whereas among GPC, Staphylococcus aureus (n=6) were the chief pathogen. Klebsiella spp. showed 100 percent resistance to ampicillin, 89-78 percent to amoxicillin/clavulanic acid and 33 percent to imipenem, however, Enterobacter spp. were resistant to ampicillin (100 percent) amoxicillin/clavulanic acid (77 percent) and imipenem (23 percent). Staphylococcus aureus showed resistance to co-amoxiclav (83 percent) and penicillin (75 percent). Practical implications – This study revealed that effective control measures must been implemented and respected by throughout the entire food chain and better surveillance studies should be performed at national level to reduce the spread of bacteria by fresh salads. Originality/value – This paper explore the high prevalence of multidrug-resistant pathogens in different salads and most of the salads were found to be unhygienic for consumption.

scholarly journals Complete Genome Sequence of Staphylococcus aureus Myophage Maine

2019 ◽  
Vol 8 (40) ◽  
Author(s):  
Russell Moreland ◽  
Abby Korn ◽  
Heather Newkirk ◽  
Mei Liu ◽  
Jason J. Gill ◽  
...  
Keyword(s):  
Staphylococcus Aureus ◽  
Genome Sequence ◽  
Complete Genome Sequence ◽  
Human Disease ◽  
Complete Genome ◽  
Multidrug Resistant ◽  
High Similarity ◽  
Promising Alternative ◽  
Content Type ◽  
Resistant Strains

Multidrug-resistant strains of Staphylococcus aureus cause serious human disease worldwide. Bacteriophages offer a promising alternative to traditional antibiotics. Here, we announce the 141,712-bp genome of S. aureus phage Maine. A myophage with 9,019-bp predicted terminal repeats and high similarity to other Staphylococcus phages, Maine falls into the Twort-like group.

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