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Targeting Siderophore-Mediated Iron Uptake in M. abscessus: A New Strategy to Limit the Virulence of Non-Tuberculous Mycobacteria

Authors :
Matteo Mori
Giovanni Stelitano
Giulia Cazzaniga
Arianna Gelain
Andrea Tresoldi
Mario Cocorullo
Martina Roversi
Laurent R. Chiarelli
Martina Tomaiuolo
Pietro Delre
Giuseppe F. Mangiatordi
Anna Griego
Loris Rizzello
Alberto Cassetta
Sonia Covaceuszach
Stefania Villa
Fiorella Meneghetti
Source :
Pharmaceutics, Vol 15, Iss 2, p 502 (2023)
Publication Year :
2023
Publisher :
MDPI AG, 2023.

Abstract

Targeting pathogenic mechanisms, rather than essential processes, represents a very attractive approach for the development of new antimycobacterial drugs. In this context, iron acquisition routes have recently emerged as potentially druggable pathways. However, the importance of siderophore biosynthesis in the virulence and pathogenicity of M. abscessus (Mab) is still poorly understood. In this study, we investigated the Salicylate Synthase (SaS) of Mab as an innovative molecular target for the development of inhibitors of siderophore production. Notably, Mab-SaS does not have any counterpart in human cells, making it an interesting candidate for drug discovery. Starting from the analysis of the binding of a series of furan-based derivatives, previously identified by our group as inhibitors of MbtI from M. tuberculosis (Mtb), we successfully selected the lead compound 1, exhibiting a strong activity against Mab-SaS (IC50 ≈ 5 µM). Computational studies characterized the key interactions between 1 and the enzyme, highlighting the important roles of Y387, G421, and K207, the latter being one of the residues involved in the first step of the catalytic reaction. These results support the hypothesis that 5-phenylfuran-2-carboxylic acids are also a promising class of Mab-SaS inhibitors, paving the way for the optimization and rational design of more potent derivatives.

Details

Language :
English
ISSN :
19994923
Volume :
15
Issue :
2
Database :
Directory of Open Access Journals
Journal :
Pharmaceutics
Publication Type :
Academic Journal
Accession number :
edsdoj.0e262c2fdf194bf3a2bdc22d88bd3f07
Document Type :
article
Full Text :
https://doi.org/10.3390/pharmaceutics15020502