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-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.

Marine Fungal Cerebroside Flavuside B Protects HaCaT Keratinocytes against Staphylococcus aureus Induced Damage

“…Sortase A and SA bacterial growth inhibitory activities were found for β-sitosterol-3-O-glucopyranoside but were not found for its aglycon sitosterol which indicates the importance of the glucoside moiety [27]. However, the literature data about cerebrosides inhibited sortase A activity are unknown [28]. If so, the present work is the first report on the ability of cerebrosides to inhibit the activity of sortase A.…”

Targeting Monoacylglycerol Lipase in Pursuit of Therapies for Neurological and Neurodegenerative Diseases

“…In this review, we focus on presenting the compounds designed during the past five years, and derivatives with proven high selectivity for MAGL, rather than other enzymes involved in endocannabinoid processing, which hold promise for optimal pharmacokinetics and improved efficacy in disorders, such as neurodegenerative diseases, chronic pain and chronic inflammatory diseases. Although we used the half maximal inhibitory concentration (IC 50 ) as an indicator of each compound’s effect on MAGL, one should consider that this parameter is only a relative indicator of the inhibitor efficacy because testing protocols often differ [ 31 ].…”

Identification of Novel Antistaphylococcal Hit Compounds Targeting Sortase A

“…Sortase A is a membrane-bound transpeptidase which catalyzes the transfer and immobilization of essential virulence factors to the surface of microorganisms. Inhibitors of sortase A affect virulence and biofilm formation, therefore decreasing selective pressure which can cause the development of antibiotic resistance [ 4 ]. Sortase A is not presented in eukaryotic organisms, hence the inhibitors of this enzyme may possibly have less toxicity for human organisms.…”