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The Gly152Val mutation possibly confers resistance to beta-lactam antibiotics in ovine Staphylococcus aureus isolates.

ABSTRACT: Background:The mecA gene is a key factor that allows bacterial cells to resist several antibiotics. Aim:This study was conducted to detect the mecA gene polymorphism in ovine wounds and its possible association with the structure and function of penicillin binding protein A2 (PBP2A). Methods:One genetic locus of 1,967 bp that covered the majority of the coding regions of the mecA gene within methicillin-resistant Staphylococcus aureus (MRSA) DNA sequences was designed. Results:In addition to standard microbiological tests, PCR-sequencing reactions and phylogenetic analyses confirmed the identity of the targeted MRSA bacteria. Seven novel missense SNPs, including N57T, N115Y, D120N, D139N, G152V, E189K, and F211V, were observed in the mecA amplicons. Multiple state-of-the-art in silico tools were utilized to assess the consequences of each observed SNP in terms of its effect on the corresponding PBP2A protein structure and function. It was shown that some MRSA isolates exhibited a highly PBP2A-damaging SNP, G152V, which showed an entirely deleterious effect on the PBP2A. Furthermore, G152V induced an alteration in the PBP2A interaction with its receptor, which presumably reduced its affinity to bind with the beta-lactams. Conclusion:The present report indicated a possible role for the observed deleterious G152V SNP in the reduction of PBP2A binding with beta-lactams, which has led to a remarkable increase in MRSA's resistance to antibiotics.

SUBMITTER: Sarhan SR

PROVIDER: S-EPMC6971359 | biostudies-literature | 2020 Jan

REPOSITORIES: biostudies-literature

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The Gly152Val mutation possibly confers resistance to beta-lactam antibiotics in ovine <i>Staphylococcus aureus</i> isolates.

Sarhan Sarhan R SR Hashim Hayder O HO Al-Shuhaib Mohammed Baqur S MBS

Open veterinary journal 20191222 4

<h4>Background</h4>The <i>mecA</i> gene is a key factor that allows bacterial cells to resist several antibiotics.<h4>Aim</h4>This study was conducted to detect the <i>mecA</i> gene polymorphism in ovine wounds and its possible association with the structure and function of penicillin binding protein A2 (PBP2A).<h4>Methods</h4>One genetic locus of 1,967 bp that covered the majority of the coding regions of the <i>mecA</i> gene within methicillin-resistant <i>Staphylococcus aureus</i> (MRSA) DNA ...[more]

PMID: 32042657

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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

The Gly152Val mutation possibly confers resistance to beta-lactam antibiotics in ovine Staphylococcus aureus isolates.

Publications

The Gly152Val mutation possibly confers resistance to beta-lactam antibiotics in ovine <i>Staphylococcus aureus</i> isolates.

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