In-Silico Identified New Natural Sortase A Inhibitors Disrupt S. aureus Biofilm Formation

• Published in: International journal of molecular sciences Vol. 21; no. 22; p. 8601
• Main Authors: Thappeta, Kishore Reddy Venkata, Zhao, Li Na, Nge, Choy Eng, Crasta, Sharon, Leong, Chung Yan, Ng, Veronica, Kanagasundaram, Yoganathan, Fan, Hao, Ng, Siew Bee
• Format: Journal Article
• Language: English
• Published: Switzerland MDPI AG 14.11.2020; MDPI
• Subjects: A549 Cells; Acids; Aminoacyltransferases - antagonists & inhibitors; Aminoacyltransferases - chemistry; Aminoacyltransferases - metabolism; Anti-Bacterial Agents - chemistry; Anti-Bacterial Agents - pharmacology; anti-biofilm activity; Antibiotics; Antiinfectives and antibacterials; Antimicrobial agents; Bacteria; Bacterial infections; Bacterial Proteins - antagonists & inhibitors; Bacterial Proteins - chemistry; Bacterial Proteins - metabolism; Biofilms; Biofilms - drug effects; Biofilms - growth & development; Cell walls; Computer Simulation; Cysteine Endopeptidases - chemistry; Cysteine Endopeptidases - metabolism; Drug resistance; Enzymatic activity; Enzyme Inhibitors - chemistry; Enzyme Inhibitors - pharmacology; Enzymes; Fibrinogen; Gram-positive bacteria; Hep G2 Cells; Humans; Ligands; Microorganisms; molecular docking; MRSA; Pathogenesis; Pathogens; Proteins; Sortase; sortase A inhibitor; Staphylococcus aureus; Staphylococcus aureus - physiology; Staphylococcus infections; Toxicity; Virulence; natural products; sortase A inhibitor; molecular docking; fibrinogen; virtual screening; MRSA; Staphylococcus aureus; anti-biofilm activity; skyrin
• ISSN: 1422-0067; 1661-6596; 1422-0067
• DOI: 10.3390/ijms21228601

Sortase A (SrtA) is a membrane-associated enzyme that anchors surface-exposed proteins to the cell wall envelope of Gram-positive bacteria such as . As SrtA is essential for Gram-positive bacterial pathogenesis but dispensable for microbial growth or viability, SrtA is considered a favorable target for the enhancement of novel anti-infective drugs that aim to interfere with key bacterial virulence mechanisms, such as biofilm formation, without developing drug resistance. Here, we used virtual screening to search an in-house natural compound library and identified two natural compounds, N1287 (Skyrin) and N2576 ((4,5-dichloro-1H-pyrrol-2-yl)-[2,4-dihydroxy-3-(4-methyl-pentyl)-phenyl]-methanone) that inhibited the enzymatic activity of SrtA. These compounds also significantly reduced the growth of but possessed moderate mammalian toxicity. Furthermore, strains treated with these compounds exhibited reduction in adherence to host fibrinogen, as well as biofilm formation. Hence, these compounds may represent an anti-infective therapy without the side effects of antibiotics.