Abstract
Staphylococcus aureus (S. aureus) is a human and other animal pathogen that contributes to the primary etiology of nosocomial pneumonia, a disease with high mortality rates and costs. Treatment of multidrug-resistant S. aureus infection is extremely challenging, and new therapeutic strategies beyond antibiotic treatment are needed. Anti-virulence agents that specifically target the molecular determinants of virulence may be a novel method for treating drug-resistant nosocomial infections. Sortase B (SrtB) is a crucial virulence factor in S. aureus and plays an important role during infection. In this study, we find that baicalin suppresses the activity of SrtB. Minimum inhibitory concentration and growth curve assays confirmed that baicalin has no anti-S. aureus properties. We performed live/dead, lactate dehydrogenase (LDH), adherence, and enzyme-linked immunosorbent assays to confirm that baicalin reduced human alveolar epithelial A549 cell injury caused by S. aureus, reduced the adherence of S. aureus to A549 cells, and significantly attenuated the inflammatory response of mouse macrophage J774 cells to S. aureus. Additionally, we were able to elucidate the binding mechanics and identify the interacting sites of baicalin and SrtB via a molecular dynamics simulation, site-directed mutagenesis, and fluorescence spectroscopy quenching. Finally, we confirmed that baicalin directly binds to the active center of SrtB, and the residues Asn92 and Tyr128 perform an important function in the interaction of SrtB and baicalin. Taken together, these data indicate that baicalin is a promising candidate to combat S. aureus infections.
Highlights
IntroductionDrug-resistant strains of S. aureus have become some of the most prevalent pathogens of community-acquired and nosocomially acquired pneumonia, giving rise to high morbidity, mortality, and cost (Cascioferro et al, 2014)
With the rapid emergence of antibiotic-resistant bacteria, new strategies aimed at targeting the virulence factors of pathogenic bacteria, rather than killing the bacteria directly, are needed to combat resistant bacterial infection (Moreillon, 2008; Benny, 2014; Mühlen and Dersch, 2016).Drug-resistant strains of S. aureus have become some of the most prevalent pathogens of community-acquired and nosocomially acquired pneumonia, giving rise to high morbidity, mortality, and cost (Cascioferro et al, 2014)
Antivirulence strategies that involve virulence factors as drug targets show promise as alternative or adjunctive modalities to combat the infections with pathogenic bacteria (Rasko and Sperandio, 2010)
Summary
Drug-resistant strains of S. aureus have become some of the most prevalent pathogens of community-acquired and nosocomially acquired pneumonia, giving rise to high morbidity, mortality, and cost (Cascioferro et al, 2014). SrtB is a transpeptidase of S. aureus; it anchors proteins to the cell wall by identifying specific sorting signals (Mazmanian et al, 2002; Zong et al, 2004; Bradshaw et al, 2015). IsdC is a substrate of SrtB and can be anchored to the cell wall by it. IsdC is an important rate-limiting protein for the process of capturing and transferring iron by S. aureus for successful infection (Maresso and Schneewind, 2006; Tiedemann et al, 2008; Villareal et al, 2011). A cysteine residue from the active site of SrtB and the cleaved substrate form an acyl intermediate, which is resolved by the amino group of pentaglycine crossbridges and is eventually anchored to the cytoderm (Marraffini and Schneewind, 2005)
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