Targeting Bacterial Sortases in Search of Anti-virulence Therapies with Low Risk of Resistance Development

• Main Authors: Georgiana Nitulescu (Author), Denisa Margina (Author), Anca Zanfirescu (Author), Octavian Tudorel Olaru (Author), George Mihai Nitulescu (Author)
• Format: Book
• Published: MDPI AG, 2021-04-01T00:00:00Z.
• Subjects: article
• Online Access: Connect to this object online.
• Notes: 10.3390/ph14050415; 1424-8247
• Keywords: Gram-positive pathogens; <i>Staphylococcus aureus</i>; <i>Streptococcus mutans</i>; covalent inhibitors; sortase A inhibitors; flavonoids; Medicine; R; Pharmacy and materia medica; RS1-441
• Source: Pharmaceuticals, Vol 14, Iss 5, p 415 (2021)

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-phenyl-benzofuran 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.