Dataset Information

Bicarbonate Resensitization of Methicillin-Resistant Staphylococcus aureus to ?-Lactam Antibiotics.

ABSTRACT: Endovascular infections caused by methicillin-resistant Staphylococcus aureus (MRSA) are a major health care concern, especially infective endocarditis (IE). Standard antimicrobial susceptibility testing (AST) defines most MRSA strains as "resistant" to ?-lactams, often leading to the 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 antistaphylococcal ?-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 ?-lactam. Mechanistically, NaHCO₃ reduced the expression of two key genes involved in the MRSA phenotype, mecA and sarA, leading to decreased production of penicillin-binding protein 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 ?-lactam therapy.

SUBMITTER: Ersoy SC

PROVIDER: S-EPMC6591647 | biostudies-literature | 2019 Jul

REPOSITORIES: biostudies-literature

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Bicarbonate Resensitization of Methicillin-Resistant <i>Staphylococcus aureus</i> to β-Lactam Antibiotics.

Ersoy Selvi C SC Abdelhady Wessam W Li Liang L Chambers Henry F HF Xiong Yan Q YQ Bayer Arnold S AS

Antimicrobial agents and chemotherapy 20190624 7

Endovascular infections caused by methicillin-resistant <i>Staphylococcus aureus</i> (MRSA) are a major health care concern, especially infective endocarditis (IE). Standard antimicrobial susceptibility testing (AST) defines most MRSA strains as "resistant" to β-lactams, often leading to the 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 distinc ...[more]

PMID: 31010857

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Project description:Methicillin-resistant Staphylococcus aureus (MRSA) resists nearly all β-lactam antibiotics that have a bactericidal activity. However, whether the empirically used β-lactams enhance MRSA pathogenicity in vivo remains unclear. In this study, we showed that a cluster of lipoprotein-like genes (lpl, sa2275 to sa2273 [sa2275-sa2273]) was upregulated in MRSA in response to subinhibitory concentrations of β-lactam induction. The increasing expression of lpl by β-lactams was directly controlled by the global regulator SarA. The β-lactam-induced Lpls stimulated the production of interleukin-6 and tumor necrosis factor alpha in RAW 264.7 macrophages. The lpl deletion mutants (N315Δlpl and USA300Δlpl) decreased the proinflammatory cytokine levels in vitro and in vivo Purified lipidated SA2275-his proteins could trigger a Toll-like-receptor-2 (TLR2)-dependent immune response in primary mouse bone marrow-derived macrophages and C57BL/6 mice. The bacterial loads of N315Δlpl in the mouse kidney were lower than those of the wild-type N315. The β-lactam-treated MRSA exacerbated cutaneous infections in both BALB/c and C57BL/6 mice, presenting increased lesion size; destroyed skin structure; and easily promoted abscess formation compared with those of the untreated MRSA. However, the size of abscesses caused by the β-lactam-treated N315 was negligibly different from those caused by the untreated N315Δlpl in C57BL/6 TLR2-/- mice. Our findings suggest that β-lactams must be used carefully because they might aggravate the outcome of MRSA infection compared to inaction in treatment.IMPORTANCE β-Lactam antibiotics are widely applied to treat infectious diseases. However, certain poor disease outcomes caused by β-lactams remain poorly understood. In this study, we have identified a cluster of lipoprotein-like genes (lpl, sa2275-sa2273) that is upregulated in the major clinically prevalent MRSA clones in response to subinhibitory concentrations of β-lactam induction. The major highlight of this work is that β-lactams stimulate the expression of SarA, which directly binds to the lpl cluster promoter region and upregulates lpl expression in MRSA. Deletion of lpl significantly decreases proinflammatory cytokine levels in vitro and in vivo The β-lactam-induced Lpls enhance host inflammatory responses by triggering the Toll-like-receptor-2-mediated expressions of interleukin-6 and tumor necrosis factor alpha. The β-lactam-induced Lpls are important virulence factors that enhance MRSA pathogenicity. These data elucidate that subinhibitory concentrations of β-lactams can exacerbate the outcomes of MRSA infection through induction of lpl controlled by the global regulator SarA.

Dataset Information

Bicarbonate Resensitization of Methicillin-Resistant Staphylococcus aureus to ?-Lactam Antibiotics.

Publications

Bicarbonate Resensitization of Methicillin-Resistant <i>Staphylococcus aureus</i> to β-Lactam Antibiotics.

Similar Datasets

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