scholarly journals β-lactam-induced cell envelope adaptations, not solely enhanced daptomycin binding, underlies daptomycin-β-lactam synergy in methicillin-resistant Staphylococcus aureus

2021 ◽  
Author(s):  
Cassandra Lew ◽  
Nagendra N. Mishra ◽  
Arnold S. Bayer ◽  
Warren E. Rose
Keyword(s):  
Staphylococcus Aureus ◽  
Surface Charge ◽  
Cell Envelope ◽  
Dependent Manner ◽  
Methicillin Resistant ◽  
Anionic Phospholipids ◽  
High Infection ◽  
Strain Dependent ◽  
Multiple Antibiotics

Methicillin-resistant Staphylococcus aureus ( MRSA ) is a serious clinical threat due to innate virulence properties, high infection rates and the ability to develop resistance to multiple antibiotics, including the lipopeptide, daptomycin ( DAP ). Acquisition of DAP resistance ( DAP-R ) in MRSA has been linked with several characteristic alterations in the cell envelope. Clinical treatment of DAP-R MRSA infections has generally involved DAP plus β-lactam combinations, although definable synergy of such combinations varies in a strain-dependent, as well as a β-lactam-dependent manner. We investigated distinct β-lactam-induced cell envelope adaptations of nine clinically-derived DAP-susceptible (DAP-S)/DAP-R strain-pairs following in vitro exposure to a panel of six standard β-lactams (nafcillin, meropenem, cloxacillin, ceftriaxone, cefaclor, or cefoxitin) which differ in their PBP-targeting profiles. In general, in both DAP-S and DAP-R strains, exposure to these β-lactams led to: i ) decreased positive surface charge; ii ) decreased CM fluidity; iii ) increased content and delocalization of anionic phospholipids (i.e., cardiolipin), with the delocalization more pronounced in DAP-R strains; and iv ) increased DAP binding in DAP-S (but not DAP-R) strains. Collectively, these results suggest β-lactam-induced alterations in at least three major cell envelope phenotypes (surface charge, membrane fluidity and cardiolipin content) could underlie improved DAP activity, not mediated solely by an increase in DAP binding. This work was presented in part at the 30th European Congress of Clinical Microbiology and Infectious Diseases ( ECCMID) Meeting, April 18-21, 2020; Poster #P3403 Note – For ease of presentation, we will utilize the terminology, “DAP-R”, instead of “DAP-nonsusceptibility”.

scholarly journals Therapeutic efficacy of BO-3482, a novel dithiocarbamate carbapenem, in mice infected with methicillin-resistant Staphylococcus aureus.

1997 ◽  
Vol 41 (10) ◽  
pp. 2278-2281 ◽  
Author(s):  
R Nagano ◽  
K Shibata ◽  
T Naito ◽  
A Fuse ◽  
K Asano ◽  
...  
Keyword(s):  
Staphylococcus Aureus ◽  
Therapeutic Efficacy ◽  
Methicillin Resistant Staphylococcus Aureus ◽  
Infection Model ◽  
Dependent Manner ◽  
Methicillin Resistant ◽  
Mrsa Strains ◽  
Systemic Infections

The in vivo activity of BO-3482, which has a dithiocarbamate chain at the C-2 position of 1beta-methyl-carbapenem, was compared with those of vancomycin and imipenem in murine models of septicemia and thigh infection with methicillin-resistant Staphylococcus aureus (MRSA). Because BO-3482 was more susceptible than imipenem to renal dehydropeptidase I in a kinetic study of hydrolysis by this renal enzyme, the therapeutic efficacy of BO-3482 was determined during coadministration with cilastatin. In the septicemia models, which involved two homogeneous MRSA strains and one heterogeneous MRSA strain, the 50% effective doses were, respectively, 4.80, 6.06, and 0.46 mg/kg of body weight for BO-3482; 5.56, 2.15, and 1.79 mg/kg for vancomycin; and >200, >200, and 15.9 mg/kg for imipenem. BO-3482 was also as effective as vancomycin in an MRSA septicemia model with mice with cyclophosphamide-induced immunosuppression. In the thigh infection model with a homogeneous MRSA strain, the bacterial counts in tissues treated with BO-3482-cilastatin were significantly reduced in a dose-dependent manner compared with the counts in those treated with vancomycin and imipenem-cilastatin (P < 0.001). These results indicate that BO-3482-cilastatin is as effective as vancomycin in murine systemic infections and is more bactericidal than vancomycin in local-tissue infections. The potent in vivo activity of BO-3482-cilastatin against such MRSA infections can be ascribed to the good in vitro anti-MRSA activity and improved pharmacokinetics in mice when BO-3482 is combined with cilastatin and to the bactericidal nature of the carbapenem.

scholarly journals In VitroCross-Resistance to Daptomycin and Host Defense Cationic Antimicrobial Peptides in Clinical Methicillin-Resistant Staphylococcus aureus Isolates

2011 ◽  
Vol 55 (9) ◽  
pp. 4012-4018 ◽  
Author(s):  
Nagendra N. Mishra ◽  
James McKinnell ◽  
Michael R. Yeaman ◽  
Aileen Rubio ◽  
Cynthia C. Nast ◽  
...  
Keyword(s):  
Staphylococcus Aureus ◽  
Cell Wall ◽  
Cell Membrane ◽  
Antimicrobial Peptides ◽  
Surface Charge ◽  
Host Defense ◽  
Cationic Antimicrobial Peptides ◽  
Methicillin Resistant ◽  
Membrane Order

ABSTRACTWe investigated the hypothesis that methicillin-resistantStaphylococcus aureus(MRSA) isolates developing reduced susceptibilities to daptomycin (DAP; a calcium-dependent molecule acting as a cationic antimicrobial peptide [CAP]) may also coevolve reducedin vitrosusceptibilities to host defense cationic antimicrobial peptides (HDPs). Ten isogenic pairs of clinical MRSA DAP-susceptible/DAP-resistant (DAPs/DAPr) strains were tested against two distinct HDPs differing in structure, mechanism of action, and origin (thrombin-induced platelet microbicidal proteins [tPMPs] and human neutrophil peptide-1 [hNP-1]) and one bacterium-derived CAP, polymyxin B (PMB). Seven of 10 DAPrstrains had point mutations in themprFlocus (with or withoutyycoperon mutations), while three DAPrstrains had neither mutation. Several phenotypic parameters previously associated with DAPrwere also examined: cell membrane order (fluidity), surface charge, and cell wall thickness profiles. Compared to the 10 DAPsparental strains, their respective DAPrstrains exhibited (i) significantly reduced susceptibility to killing by all three peptides (P< 0.05), (ii) increased cell membrane fluidity, and (iii) significantly thicker cell walls (P< 0.0001). There was no consistent pattern of surface charge profiles distinguishing DAPsand DAPrstrain pairs. Reducedin vitrosusceptibility to two HDPs and one bacterium-derived CAP tracked closely with DAPrin these 10 recent MRSA clinical isolates. These results suggest that adaptive mechanisms involved in the evolution of DAPralso provide MRSA with enhanced survivability against HDPs. Such adaptations appear to correlate with MRSA variations in cell membrane order and cell wall structure. DAPrstrains with or without mutations in themprFlocus demonstrated significant cross-resistance profiles to these unrelated CAPs.

scholarly journals Observed Antagonistic Effect of Linezolid on Daptomycin or Vancomycin Activity against Biofilm-Forming Methicillin-Resistant Staphylococcus aureus in anIn VitroPharmacodynamic Model

2015 ◽  
Vol 59 (12) ◽  
pp. 7790-7794 ◽  
Author(s):  
Megan K. Luther ◽  
Kerry L. LaPlante
Keyword(s):  
Staphylococcus Aureus ◽  
Methicillin Resistant Staphylococcus Aureus ◽  
Clinical Investigation ◽  
Antagonistic Effect ◽  
Free Drug ◽  
Methicillin Resistant ◽  
Content Type ◽  
Drug Concentrations ◽  
Strain Dependent

ABSTRACTPharmacodynamic activity in antibiotic combinations of daptomycin, vancomycin, and linezolid was investigated in a 48-hin vitropharmacodynamic model. Using human-simulated free drug concentrations, activity against clinical biofilm-forming methicillin-resistantStaphylococcus aureusisolates was evaluated. Linezolid antagonized vancomycin activity at 24 and 48 h. Linezolid antagonized daptomycin at 24 and 48 h depending on dose and strain. Adding daptomycin increased vancomycin activity at 48 h (P< 0.03). These results may be strain dependent and require further clinical investigation.

scholarly journals Analysis of Cell Membrane Characteristics of In Vitro-Selected Daptomycin-Resistant Strains of Methicillin-Resistant Staphylococcus aureus

2009 ◽  
Vol 53 (6) ◽  
pp. 2312-2318 ◽  
Author(s):  
Nagendra N. Mishra ◽  
Soo-Jin Yang ◽  
Ayumi Sawa ◽  
Aileen Rubio ◽  
Cynthia C. Nast ◽  
...  
Keyword(s):  
Staphylococcus Aureus ◽  
Cell Membrane ◽  
Surface Charge ◽  
Parental Strain ◽  
Phospholipid Content ◽  
Surface Binding ◽  
Methicillin Resistant ◽  
Positive Surface Charge ◽  
Vancomycin Mics

ABSTRACT Our previous studies of clinical daptomycin-resistant (Dapr) Staphylococcus aureus strains suggested that resistance is linked to the perturbations of several key cell membrane (CM) characteristics, including the CM order (fluidity), phospholipid content and asymmetry, and relative surface charge. In the present study, we examined the CM profiles of a well-known methicillin-resistant Staphylococcus aureus (MRSA) strain (MW2) after in vitro selection for DAP resistance by a 20-day serial passage in sublethal concentrations of DAP. Compared to levels for the parental strain, Dapr strains exhibited (i) decreased CM fluidity, (ii) the increased synthesis of total lysyl-phosphatidylglycerol (LPG), (iii) the increased flipping of LPG to the CM outer bilayer, and (iv) the increased expression of mprF, the gene responsible for the latter two phenotypes. In addition, we found that the expression of the dlt operon, which also increases positive surface charge, was enhanced in the Dapr mutants. These phenotypic and genotypic changes correlated with reduced DAP surface binding, mirroring observations made in clinical Dapr isolates. In this strain, serial exposure to DAP induced an increase in vancomycin MICs into the vancomycin-intermediate S. aureus (VISA) range (4 μg/ml) in parallel with increasing DAP MICs. Also, this Dapr strain exhibited significantly thicker cell walls than the parental strain, potentially correlating with the coevolution of the VISA phenotype and implicating cell wall structure and/or function in the Dapr phenotype. Importantly, despite the overexpression of mprF and dlt, the relative net positive surface charge was decreased in the Dapr mutants, suggesting that other factors contribute to the surface charge alterations and that a simple charge repulsion mechanism could not entirely explain the Dapr phenotype in these strains.

scholarly journals Group V Phospholipase A2 Mediates Endothelial Dysfunction and Acute Lung Injury Caused by Methicillin-Resistant Staphylococcus aureus

Cells ◽  
2021 ◽  
Vol 10 (7) ◽  
pp. 1731
Author(s):  
Yu Maw Htwe ◽  
Huashan Wang ◽  
Patrick Belvitch ◽  
Lucille Meliton ◽  
Mounica Bandela ◽  
...  
Keyword(s):  
Staphylococcus Aureus ◽  
Acute Lung Injury ◽  
Endothelial Dysfunction ◽  
Lung Injury ◽  
Phospholipase A2 ◽  
Methicillin Resistant Staphylococcus Aureus ◽  
Group V ◽  
Methicillin Resistant

Lung endothelial dysfunction is a key feature of acute lung injury (ALI) and clinical acute respiratory distress syndrome (ARDS). Previous studies have identified the lipid-generating enzyme, group V phospholipase A2 (gVPLA2), as a mediator of lung endothelial barrier disruption and inflammation. The current study aimed to determine the role of gVPLA2 in mediating lung endothelial responses to methicillin-resistant Staphylococcus aureus (MRSA, USA300 strain), a major cause of ALI/ARDS. In vitro studies assessed the effects of gVPLA2 inhibition on lung endothelial cell (EC) permeability after exposure to heat-killed (HK) MRSA. In vivo studies assessed the effects of intratracheal live or HK-MRSA on multiple indices of ALI in wild-type (WT) and gVPLA2-deficient (KO) mice. In vitro, HK-MRSA increased gVPLA2 expression and permeability in human lung EC. Inhibition of gVPLA2 with either the PLA2 inhibitor, LY311727, or with a specific monoclonal antibody, attenuated the barrier disruption caused by HK-MRSA. LY311727 also reduced HK-MRSA-induced permeability in mouse lung EC isolated from WT but not gVPLA2-KO mice. In vivo, live MRSA caused significantly less ALI in gVPLA2 KO mice compared to WT, findings confirmed by intravital microscopy assessment in HK-MRSA-treated mice. After targeted delivery of gVPLA2 plasmid to lung endothelium using ACE antibody-conjugated liposomes, MRSA-induced ALI was significantly increased in gVPLA2-KO mice, indicating that lung endothelial expression of gVPLA2 is critical in vivo. In summary, these results demonstrate an important role for gVPLA2 in mediating MRSA-induced lung EC permeability and ALI. Thus, gVPLA2 may represent a novel therapeutic target in ALI/ARDS caused by bacterial infection.

scholarly journals In Vitro activity of a Novel Benzoquinolizine Antibiotic, Levonadifloxacin (WCK 771) against Blood Stream Gram-Positive Isolates from a Tertiary Care Hospital

2020 ◽  
Vol 12 (03) ◽  
pp. 230-232
Author(s):  
Dhruv Mamtora ◽  
Sanjith Saseedharan ◽  
Ritika Rampal ◽  
Prashant Joshi ◽  
Pallavi Bhalekar ◽  
...  
Keyword(s):  
Staphylococcus Aureus ◽  
Tertiary Care Hospital ◽  
Tertiary Care ◽  
Blood Stream ◽  
Tolerability Profile ◽  
Care Hospital ◽  
Coagulase Negative Staphylococci ◽  
Gram Positive ◽  
Methicillin Resistant

Abstract Background Blood stream infections (BSIs) due to Gram-positive pathogens such as methicillin-resistant Staphylococcus aureus (MRSA) are associated with high mortality ranging from 10 to 60%. The current anti-MRSA agents have limitations with regards to safety and tolerability profile which limits their prolonged usage. Levonadifloxacin and its oral prodrug alalevonadifloxacin, a novel benzoquinolizine antibiotic, have recently been approved for acute bacterial skin and skin structure infections including diabetic foot infections and concurrent bacteremia in India. Methods The present study assessed the potency of levonadifloxacin, a novel benzoquinolizine antibiotic, against Gram-positive blood stream clinical isolates (n = 31) collected from January to June 2019 at a tertiary care hospital in Mumbai, India. The susceptibility of isolates to antibacterial agents was defined following the Clinical and Laboratory Standard Institute interpretive criteria (M100 E29). Results High prevalence of MRSA (62.5%), quinolone-resistant Staphylococcus aureus (QRSA) (87.5%), and methicillin-resistant coagulase-negative staphylococci (MR-CoNS) (82.35%) were observed among bacteremic isolates. Levonadifloxacin demonstrated potent activity against MRSA, QRSA, and MR-CoNS strains with significantly lower minimum inhibitory concentration MIC50/90 values of 0.5/1 mg/L as compared with levofloxacin (8/32 mg/L) and moxifloxacin (2/8 mg/L). Conclusion Potent bactericidal activity coupled with low MICs support usage of levonadifloxacin for the management of BSIs caused by multidrug resistant Gram-positive bacteria.

scholarly journals In VitroActivities of Daptomycin-, Vancomycin-, and Teicoplanin-Loaded Polymethylmethacrylate against Methicillin-Susceptible, Methicillin-Resistant, and Vancomycin-Intermediate Strains of Staphylococcus aureus

2011 ◽  
Vol 55 (12) ◽  
pp. 5480-5484 ◽  
Author(s):  
Yuhan Chang ◽  
Wen-Chien Chen ◽  
Pang-Hsin Hsieh ◽  
Dave W. Chen ◽  
Mel S. Lee ◽  
...  
Keyword(s):  
Staphylococcus Aureus ◽  
High Performance ◽  
Low Dose ◽  
Antibacterial Activities ◽  
High Dose ◽  
Bone Cements ◽  
Antibacterial Effects ◽  
Methicillin Resistant ◽  
Content Type

ABSTRACTThe objective of this study was to evaluate the antibacterial effects of polymethylmethacrylate (PMMA) bone cements loaded with daptomycin, vancomycin, and teicoplanin against methicillin-susceptibleStaphylococcus aureus(MSSA), methicillin-resistantStaphylococcus aureus(MRSA), and vancomycin-intermediateStaphylococcus aureus(VISA) strains. Standardized cement specimens made from 40 g PMMA loaded with 1 g (low-dose), 4 g (middle-dose) or 8 g (high-dose) antibiotics were tested for elution characteristics and antibacterial activities. The patterns of release of antibiotics from the cement specimens were evaluated usingin vitrobroth elution assay with high-performance liquid chromatography. The activities of broth elution fluid against differentStaphylococcus aureusstrains (MSSA, MRSA, and VISA) were then determined. The antibacterial activities of all the tested antibiotics were maintained after being mixed with PMMA. The cements loaded with higher dosages of antibiotics showed longer elution periods. Regardless of the antibiotic loading dose, the teicoplanin-loaded cements showed better elution efficacy and provided longer inhibitory periods against MSSA, MRSA, and VISA than cements loaded with the same dose of vancomycin or daptomycin. Regarding the choice of antibiotics for cement loading in the treatment ofStaphylococcus aureusinfection, teicoplanin was superior in terms of antibacterial effects.

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