Targeting bacterial sortases in search of anti-virulence therapies with low risk of resistance development

Abstract

Increasingly ineffective antibiotics and rapid spread of multi-and pan-resistant bacteria represent a global health threat; hence, the need of developing new antimicrobial medicines. A first step in this direction is identifying new molecular targets, such as virulence factors. Sortase A represents a virulence factor essential for the pathogenesis of Gram-positive pathogens, some of which have a high risk for human health. We present here an exhaustive collection of sortases inhibitors grouped by relevant chemical features: vinyl sulfones, 3-aryl acrylic acids and derivatives, flavonoids, naphtoquinones, anthraquinones, indoles, pyrrolomycins, isoquinoline derivatives, aryl β-aminoethyl ketones, pyrazolethiones, pyridazinones, benzisothiazolinones, 2-phenyl-benzoxazole and 2-phenylbenzofuran derivatives, thiadiazoles, triazolothiadiazoles, 2-(2-phenylhydrazinylidene)alkanoic acids, and 1,2,4-thiadiazolidine-3,5-dione. This review focuses on highlighting their structure–activity relationships, using the half maximal inhibitory concentration (IC50 ), when available, as an indicator of each compound effect on a specific sortase. The information herein is useful for acquiring knowledge on diverse natural and synthetic sortases inhibitors scaffolds and for understanding the way their structural variations impact IC50 . It will hopefully be the inspiration for designing novel effective and safe sortase inhibitors in order to create new anti-infective compounds and to help overcoming the current worldwide antibiotic shortage.