Dataset Information

Peptidoglycan Cross-Linking Preferences of Staphylococcus aureus Penicillin-Binding Proteins Have Implications for Treating MRSA Infections.

ABSTRACT: Methicillin-resistant Staphylococcus aureus (MRSA) infections are a global public health problem. MRSA strains have acquired a non-native penicillin-binding protein called PBP2a that cross-links peptidoglycan when the native S. aureus PBPs are inhibited by ?-lactams. It has been proposed that the native S. aureus PBPs can use cell wall precursors having different glycine branch lengths (penta-, tri-, or monoglycine), while PBP2a can only cross-link peptidoglycan strands bearing a complete pentaglycine branch. This hypothesis has never been tested because the necessary substrates have not been available. Here, we compared the ability of PBP2a and two native S. aureus transpeptidases to cross-link peptidoglycan strands bearing different glycine branches. We show that purified PBP2a can cross-link glycan strands bearing penta- and triglycine, but not monoglycine, and experiments in cells provide support for these findings. Because PBP2a cannot cross-link peptidoglycan containing monoglycine, this study implicates the enzyme (FemA) that extends the monoglycine branch to triglycine on Lipid II as an ideal target for small molecules that restore sensitivity of MRSA to ?-lactams.

SUBMITTER: Srisuknimit V

PROVIDER: S-EPMC5613940 | biostudies-literature | 2017 Jul

REPOSITORIES: biostudies-literature

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Peptidoglycan Cross-Linking Preferences of Staphylococcus aureus Penicillin-Binding Proteins Have Implications for Treating MRSA Infections.

Srisuknimit Veerasak V Qiao Yuan Y Schaefer Kaitlin K Kahne Daniel D Walker Suzanne S

Journal of the American Chemical Society 20170711 29

Methicillin-resistant Staphylococcus aureus (MRSA) infections are a global public health problem. MRSA strains have acquired a non-native penicillin-binding protein called PBP2a that cross-links peptidoglycan when the native S. aureus PBPs are inhibited by β-lactams. It has been proposed that the native S. aureus PBPs can use cell wall precursors having different glycine branch lengths (penta-, tri-, or monoglycine), while PBP2a can only cross-link peptidoglycan strands bearing a complete pentag ...[more]

PMID: 28691491

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Project description:Staphylococcus aureus bacteraemia is a serious infection associated with significant complications, including recurrence of bacteraemia, endocarditis and metastatic foci of infection. The management of these patients is often complex, involving appropriate source control, a thorough review and investigations to exclude metastatic foci and infective endocarditis. Additionally, a prolonged course of intravenous antibiotics is often required. As part of our quality improvement project, the following five aspects were evaluated in 56 patients with S. aureus bacteraemia at two District General Hospitals: 1) adequate and timely removal of the source of bacteraemia, 2) echocardiography to exclude endocarditis, 3) repeat blood culture to prove clearance of bacteraemia, 4) adequate duration and choice of antibiotics and 5) documentation of bacteraemia in the discharge summary. After an initial review revealed several areas for improvement, we instituted five Plan-Do-Study-Act learning cycles which involved: teaching microbiology trainees and junior doctors, improving clinical liaison and communication between the microbiology team and clinicians, as well as a clinical review of patients by the microbiology team where appropriate. The post-intervention review evaluated 24 patients with S. aureus bacteraemia between November 2012 and May 2013. The proportion of patients undergoing an echocardiogram improved from 49% to 88%. Another marked improvement was seen in the timely obtaining of clearance blood cultures, with 88% of patients having clearance blood cultures within the 2-4 day window, compared to 56% pre-intervention. 70% of patients with uncomplicated S. aureus bacteraemia received an appropriate antibiotic course post-intervention, compared with 59% pre-intervention. Documentation of the S. aureus bacteraemia in the discharge summary improved from 65% to 75%. The support of the entire microbiology team was pivotal in the successful outcome of the quality improvement project.

Dataset Information

Peptidoglycan Cross-Linking Preferences of Staphylococcus aureus Penicillin-Binding Proteins Have Implications for Treating MRSA Infections.

Publications

Peptidoglycan Cross-Linking Preferences of Staphylococcus aureus Penicillin-Binding Proteins Have Implications for Treating MRSA Infections.

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