Biology subjects

Xiong, Y. Q.

Publications and source records attributed to Xiong, Y. Q..

3 recordsLinked to original sources

bioRxiv2021

Efficacy of Anti-Staphylococcal Lysin, LSVT-1701, in Combination with Daptomycin in Experimental Left-Sided Infective Endocarditis Due to Methicillin-Resistant Staphylococcus aureus (MRSA)

MRSA endovascular infections are frequently recalcitrant to treatment with standard-of-care antibiotics. Anti-staphylococcal phage lysins represent important candidate adjunctive agents against invasive MRSA infections because of both their microbicidal and anti-biofilm properties. We utilized the rabbit model of aortic valve infective endocarditis (using the prototype MRSA strain, MW2) to examine the combined efficacy of the lysin, LSVT-1701, plus daptomycin. LSVT-1701 was given at two dose-regimens (32.5 mg/kg and 50 mg/kg) with different dose-durations (single dose vs daily dose for 2 d vs daily dose for 4 d); daptomycin was given at a sub-lethal daily dose of 4 mg/kg for 4 d to maximize potential synergistic interaction outcomes. The combination of LSVT-1701 plus daptomycin was highly effective at reducing target tissue MRSA counts (cardiac vegetations, kidneys, and spleen), especially when the lysin was given for multiple days and/or at higher daily doses. Of importance, when given for four daily doses, both lysin dose-regimens in combination with daptomycin sterilized all target tissues. These findings suggest that LSVT-1701 warrants further clinical evaluation as adjunctive therapy for the treatment of invasive MRSA infections.

microbiology↗

bioRxiv2019

Ability of Bicarbonate Supplementation to Sensitize Selected Methicillin-Resistant Staphylococcus aureus (MRSA) Strains to β-Lactam Antibiotics in an Ex Vivo Simulated Endocardial Vegetation Model

Supplementation of standard growth media (cation-adjusted Mueller-Hinton Broth [CAMHB]) with bicarbonate (NaHCO3) significantly increases {beta}-lactam susceptibility of selected MRSA strains (\"NaHCO3-responsive\"). This \"sensitization\" phenomenon translated to enhanced {beta}-lactam efficacy in a rabbit model of endocarditis. The present study evaluated NaHCO3-mediated {beta}-lactam MRSA sensitization using an ex vivo pharmacodynamic model, featuring simulated endocardial vegetations (SEVs), to more closely mimic the host microenvironment. Four previously described MRSA strains were used: two each exhibiting in vitro \"NaHCO3-responsive\" or \"NaHCO3-nonresponsive\" phenotypes. Cefazolin (CFZ) and oxacillin (OXA) were evaluated in CAMHB{+/-}NaHCO3. Intra-SEV MRSA killing was determined over 72 hr exposure. In both NaHCO3-responsive strains, supplementation with 25 mM or 44 mM NaHCO3 significantly reduced {beta}-lactam MICs to below the OXA susceptibility breakpoint ([≤] 4 mg/L) resulting in bactericidal activity ([≥] 3 log kill) in the model for both OXA and CFZ. In contrast, neither in vitro-defined NaHCO3-nonresponsive MRSA strains showed significant sensitization in the SEV model to either {beta}-lactam. At both NaHCO3 concentrations, the fractional time-above-MIC was >50% for both CFZ and OXA in the NaHCO3-responsive MRSA. Also, in RPMI+10% LB media (proposed as a more host-mimicking microenvironment and containing 25 mM NaHCO3), both CFZ and OXA exhibited enhanced bactericidal activity against each NaHCO3-responsive strain in the SEV model. Neither CFZ nor OXA exposures selected for high-level {beta}-lactam-resistant mutants within SEVs. Thus, in this ex vivo model of endocarditis, in the presence of NaHCO3 supplementation, both CFZ and OXA are highly active against MRSA strains that demonstrate similar enhanced susceptibility in NaHCO3-supplemented media in vitro.

microbiology↗

bioRxiv2019

Bicarbonate Resensitization of Methicillin-Resistant Staphylococcus aureus to β-Lactam Antibiotics

Endovascular infections caused by methicillin-resistant Staphylococcus aureus (MRSA) are a major healthcare concern, especially infective endocarditis (IE). Standard antimicrobial susceptibility testing (AST) defines most MRSA strains as resistant to {beta}-lactams, often leading to use of costly and/or toxic treatment regimens. In this investigation, five prototype MRSA strains, representing the range of genotypes in current clinical circulation, were studied. We identified two distinct MRSA phenotypes upon AST using standard media, with or without sodium bicarbonate (NaHCO3) supplementation: one highly susceptible to the anti-staphylococcal {beta}-lactams, oxacillin and cefazolin ( NaHCO3-responsive) and one resistant to such agents ( NaHCO3-nonresponsive). These phenotypes accurately predicted clearance profiles of MRSA from target tissues in experimental MRSA IE treated with each {beta}-lactam. Mechanistically, NaHCO3 reduced expression of two key genes involved in the MRSA phenotype, mecA and sarA, leading to decreased production of penicillin-binding protein (PBP) 2a (that mediates methicillin resistance), in NaHCO3-responsive (but not in NaHCO3-nonresponsive) strains. Moreover, both cefazolin and oxacillin synergistically killed NaHCO3-responsive strains in the presence of the host defense antimicrobial peptide (LL-37) in NaHCO3-supplemented media. These findings suggest that AST of MRSA strains in NaHCO3-containing media may potentially identify infections caused by NaHCO3-responsive strains that are appropriate for {beta}-lactam therapy.

microbiology↗