title: Sortase A: an ideal target for anti-virulence drug development.
abstract: Sortase A is a membrane enzyme responsible for the anchoring of surface-exposed proteins to the cell wall envelope of Gram-positive bacteria. As a well-studied member of the sortase subfamily catalysing the cell wall anchoring of important virulence factors to the surface of staphylococci, enterococci and streptococci, sortase A plays a critical role in Gram-positive bacterial pathogenesis. It is thus considered a promising target for the development of new anti-infective drugs that aim to interfere with important Gram-positive virulence mechanisms, such as adhesion to host tissues, evasion of host defences, and biofilm formation. The additional properties of sortase A as an enzyme that is not required for Gram-positive bacterial growth or viability and is conveniently located on the cell membrane making it more accessible to inhibitor targeting, constitute additional reasons reinforcing the view that sortase A is an ideal target for anti-virulence drug development. Many inhibitors of sortase A have been identified to date using high-throughput or in silico screening of compound libraries (synthetic or natural), and while many have proved useful tools for probing the action model of the enzyme, several are also promising candidates for the development into potent inhibitors. This review is focused on the most promising sortase A inhibitor compounds that are currently in development as leads towards a new class of anti-infective drugs that are urgently needed to help combat the alarming increase in antimicrobial resistance.
authors.affiliation: Department of Biological, Chemical and Pharmaceutical Science and Technology, Università degli Studi di Palermo, Via Archirafi 32, Palermo, Italy. Electronic address: stellamaria.cascioferro@unipa.it.
authors.forename: Stella
authors.initials: S
authors.lastname: Cascioferro
authors.affiliation: Institute of Health and Biomedical Innovation, School of Biomedical Sciences, Faculty of Health, Queensland University of Technology, Kelvin Grove, QLD 4059, Australia.
authors.forename: Makrina
authors.initials: M
authors.lastname: Totsika
authors.affiliation: Department of Biological, Chemical and Pharmaceutical Science and Technology, Università degli Studi di Palermo, Via Archirafi 32, Palermo, Italy.
authors.forename: Domenico
authors.initials: D
authors.lastname: Schillaci
mesh_terms: D019881:Aminoacyltransferases / Q000037:antagonists & inhibitors* / Q000378:metabolism*; D000900:Anti-Bacterial Agents / Q000302:isolation & purification* / Q000494:pharmacology*; D001426:Bacterial Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism*; D003546:Cysteine Endopeptidases / Q000378:metabolism*; D055808:Drug Discovery / Q000379:methods*; D006094:Gram-Positive Bacteria / Q000187:drug effects* / Q000201:enzymology*; D014774:Virulence / Q000187:drug effects; D037521:Virulence Factors / Q000037:antagonists & inhibitors / Q000378:metabolism
chemical_list: D000900:Anti-Bacterial Agents; D001426:Bacterial Proteins; D037521:Virulence Factors; D019881:Aminoacyltransferases; C120542:sortase A; D003546:Cysteine Endopeptidases
keywords: Antimicrobial resistance; Antivirulence drugs; Gram-positive pathogens; Sortase A; Sortase A inhibitors