Identification of cell wall synthesis inhibitors active against Mycobacterium tuberculosis by competitive activity-based protein profiling
Year: 2021
Type: article
Abstract: The identification and validation of a small molecule's targets is a major bottleneck in the discovery process for tuberculosis antibiotics. Activity-based protein profiling (ABPP) is an efficient tool for determining a small molecule's targets within complex proteomes. However, how target inhibition relates to biological activity is often left unexplored. Here, we study the effects of 1,2,3-triazole ureas on Mycobacterium tuberculosis (Mtb). After screening ∼200 compounds, we focus on 4 compounds that form a structure-activity series. The compound with negligible activity reveals targets, the inhibition of which is functionally less relevant for Mtb growth and viability, an aspect not addressed in other ABPP studies. Biochemistry, computational docking, and morphological analysis confirms that active compounds preferentially inhibit serine hydrolases with cell wall and lipid metabolism functions and that disruption of the cell wall underlies biological activity. Our findings show that ABPP identifies the targets most likely relevant to a compound's antibacterial activity.
Source: Cell chemical biology
Language: English
Subfield: Infectious Diseases
Field: Medicine
Domain: Health Sciences
Open Access status: hybrid
Estimated APC paid: $9,353
Funders: Bill and Melinda Gates Foundation, American Lung Association, Aix-Marseille Université, Agence Nationale de la Recherche, Centre National de la Recherche Scientifique, National Institutes of Health, National Institute of General Medical Sciences, National Institute of Allergy and Infectious Diseases, U.S. National Library of Medicine
Awards: G1216644687, SBU Chemistry-Biology Interface Training Program, G1485599380, G1535256716, G1641859338, G1901566080, G198321885, Untangling the Inner Workings of the Mycobacterial Cell Envelope, G2417961951, G2518323659, G2617520305, G2623691080, G2757954258, G2846889671, G2880961930, G3097532349, G3804882434, G3880744747, G3904855383, G4085066133, G4404464909, Functional aspects and physisopathological impact of intracytoplasmic lipid inclusions in mycobacteria, G4653802397, G4803225050, New selective Inhibitors for deciphering Lipid metabolism and virulence in M. tb, G5321193773, G5355973494, G5467881811, Medical Scientist Training Program, G5730494503, G5738290261, G5995673137, G606434549, G608176233, G6097468659, G6235947804, G663646255, Single-cell factors of tuberculosis drug tolerance during adaptation to environmental stressors, G6661434942, G6807347822, G6890463935, G702398518, G7063100265, G7079796644, G7204863052, G7348613980, G7497719802, Quantitative Design of Multi-drug Regiments for Tuberculosis, G7761801572, G7885520707, G8105297515, G8108643518, G8273384904, G830604292, G8485645513, G8743768569, Identification and inhibition of hydrolases in Mycobacterium tuberculosis, G8859138734, G8974851720, G9000063071, G9000184642, G954187991
OpenAlex ID: W3202861230