Tuberculosis (TB) causes millions of deaths every year, ranking as one of the most dangerous infectious diseases worldwide. Because several pathogenic strains of M. tuberculosis (Mtb) have developed resistance against most of the established anti-TB drugs, new therapeutic options are urgently needed. An attractive target for the development of new anti-TB agents is the salicylate synthase MbtI, the first enzyme of the mycobacterial siderophore biochemical machinery, absent in human cells. In this work, a set of analogues of 5-(3-cyanophenyl)furan-2-carboxylic acid (I), the most potent MbtI inhibitor identified to date, was synthesized, characterized, and tested to further elucidate the structural requirements for achieving an efficient MbtI inhibition and potent antitubercular activity. The structure-activity relationships (SAR) discussed herein evidenced the importance of the side chain linked to the phenyl moiety to improve the in vitro antimycobacterial activity. In detail, 1f emerged as the most effective analogue against the pathogen, acting without cytotoxicity issues. To deepen the understanding of its mechanism of action, we established a fluorescence-based screening test to quantify the pathogen infectivity within host cells, using MPI-2 murine cells, a robust surrogate for alveolar macrophages. The set-up of the new assay demonstrates significant potential to accelerate the discovery of new anti-TB drugs.

Synthesis and Assessment of the In Vitro and Ex Vivo Activity of Salicylate Synthase (Mbti) Inhibitors as New Candidates for the Treatment of Mycobacterial Infections / M. Mori, G. Stelitano, A. Griego, L.R. Chiarelli, G. Cazzaniga, A. Gelain, E. Pini, M. Camera, P. Canzano, A. Fumagalli, E. Scarpa, C. Cordiglieri, L. Rizzello, S. Villa, F. Meneghetti. - In: PHARMACEUTICALS. - ISSN 1424-8247. - 15:8(2022 Aug 11), pp. 992.1-992.22. [10.3390/ph15080992]

Synthesis and Assessment of the In Vitro and Ex Vivo Activity of Salicylate Synthase (Mbti) Inhibitors as New Candidates for the Treatment of Mycobacterial Infections

M. Mori
Primo
;
A. Griego;G. Cazzaniga;A. Gelain;E. Pini;M. Camera;P. Canzano;A. Fumagalli;E. Scarpa;L. Rizzello
;
S. Villa
Penultimo
;
F. Meneghetti
Ultimo
2022-08-11

Abstract

Tuberculosis (TB) causes millions of deaths every year, ranking as one of the most dangerous infectious diseases worldwide. Because several pathogenic strains of M. tuberculosis (Mtb) have developed resistance against most of the established anti-TB drugs, new therapeutic options are urgently needed. An attractive target for the development of new anti-TB agents is the salicylate synthase MbtI, the first enzyme of the mycobacterial siderophore biochemical machinery, absent in human cells. In this work, a set of analogues of 5-(3-cyanophenyl)furan-2-carboxylic acid (I), the most potent MbtI inhibitor identified to date, was synthesized, characterized, and tested to further elucidate the structural requirements for achieving an efficient MbtI inhibition and potent antitubercular activity. The structure-activity relationships (SAR) discussed herein evidenced the importance of the side chain linked to the phenyl moiety to improve the in vitro antimycobacterial activity. In detail, 1f emerged as the most effective analogue against the pathogen, acting without cytotoxicity issues. To deepen the understanding of its mechanism of action, we established a fluorescence-based screening test to quantify the pathogen infectivity within host cells, using MPI-2 murine cells, a robust surrogate for alveolar macrophages. The set-up of the new assay demonstrates significant potential to accelerate the discovery of new anti-TB drugs.
drug development; drug resistance; furan; murine alveolar-like macrophages; mycobactins; siderophores; tuberculosis;
Settore CHIM/08 - Chimica Farmaceutica
H2020_ERC20AARNO_01 - Pandemics Outbreaks Rationalized: towards a universal therapy to eliminate intracellular pathogens and drug resistance (PANDORA) - RIZZELLO, LORIS - H2020_ERC - Horizon 2020_Europern Research Council - 2020
PRIN202022LRIZZ_01 - Deciphering host-pathogen interactions to eradicate intracellular mycobacteria pathogens: key drivers to design new precision nanomedicine tools - RIZZELLO, LORIS - PRIN2020 - PRIN bando 2020 - 2022
CAR_ERC20AARNO_01 - Meccanobiologia delle infezioni: un nuovo strumento per eliminare patogeni intracellulari - ARNOLDI, ANNA - CAR_ERC - CARIPLO ATTRATTIVITA' ERC (SOTTOMISURE A, B, C) - 2020
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Utilizza questo identificativo per citare o creare un link a questo documento: http://hdl.handle.net/2434/936726
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