Molecular basis and therapeutic potential of sortase A inhibitors as new antibiotics against MDR pathogens

Attaching proteins to the cell surface presents a technical challenge to Gram-positive bacteria. A class of enzymes called sortases solves this challenge by covalently anchoring proteins, including an arsenal of virulence factors, to the cell wall. Most Gram-positive bacteria have multiple critical factors that are anchored in this manner and, coupled with the extracellular location of this reaction, make sortase an attractive target for the development of antibiotics. However, since sortase is neither essential nor itself a virulence factor, it is a very different sort of target compared to those investigated in other antibiotic strategies. This review explores the challenges of treating infection by Gram-positive pathogens, the importance of sortase-anchored proteins in the host-pathogen interaction and the known and probable antimicrobial effects of sortase inhibition for infections by Staphylococcus aureus, Streptococcus pyogenes, Bacillus anthracis, Listeria monocytogenes and other Gram-positive pathogens.