2. Academic Validation
  3. Structural basis for specific inhibition of salicylate synthase from Mycobacterium abscessus

Structural basis for specific inhibition of salicylate synthase from Mycobacterium abscessus

  • Eur J Med Chem. 2023 Dec 20:265:116073. doi: 10.1016/j.ejmech.2023.116073.
Matteo Mori 1,  Mario Cocorullo 2,  Andrea Tresoldi 1,  Giulia Cazzaniga 1,  Arianna Gelain 1,  Giovanni Stelitano 2,  Laurent R Chiarelli 2,  Martina Tomaiuolo 3,  Pietro Delre 4,  Giuseppe F Mangiatordi 4,  Mariangela Garofalo 5,  Alberto Cassetta 3,  Sonia Covaceuszach 6,  Stefania Villa 7,  Fiorella Meneghetti 1
Affiliations

Affiliations

  • 1 Department of Pharmaceutical Sciences, University of Milan, Via L. Mangiagalli 25, 20133, Milano, Italy.
  • 2 Department of Biology and Biotechnology "Lazzaro Spallanzani", University of Pavia, Via A. Ferrata 9, 27100, Pavia, Italy.
  • 3 Institute of Crystallography, National Research Council, Trieste Outstation, Area Science Park - Basovizza, S.S.14 - Km. 163.5, 34149, Trieste, Italy.
  • 4 Institute of Crystallography, National Research Council, Via G. Amendola 122/o, 70126, Bari, Italy.
  • 5 Department of Pharmaceutical and Pharmacological Sciences, University of Padova, via F. Marzolo 5, 35131, Padova, Italy.
  • 6 Institute of Crystallography, National Research Council, Trieste Outstation, Area Science Park - Basovizza, S.S.14 - Km. 163.5, 34149, Trieste, Italy. Electronic address: sonia.covaceuszach@ic.cnr.it.
  • 7 Department of Pharmaceutical Sciences, University of Milan, Via L. Mangiagalli 25, 20133, Milano, Italy. Electronic address: stefania.villa@unimi.it.
PMID: 38169270 DOI: 10.1016/j.ejmech.2023.116073
Abstract

Blocking iron uptake and metabolism has been emerging as a promising therapeutic strategy for the development of novel antimicrobial compounds. Like all mycobacteria, M. abscessus (Mab) has evolved several countermeasures to scavenge iron from host carrier proteins, including the production of siderophores, which play a crucial role in these processes. In this study, we solved, for the first time, the crystal structure of Mab-SaS, the first Enzyme involved in the biosynthesis of siderophores. Moreover, we screened a small, focused library and identified a compound exhibiting a potent inhibitory effect against Mab-SaS (IC50 ≈ 2 μM). Its binding mode was investigated by means of Induced Fit Docking simulations, performed on the crystal structure presented herein. Furthermore, cytotoxicity data and pharmacokinetic predictions revealed the safety and drug-likeness of this class of compounds. Finally, the crystallographic data were used to optimize the model for future virtual screening campaigns. Taken together, the findings of our study pave the way for the identification of potent Mab-SaS inhibitors, based on both established and unexplored chemotypes.

Keywords

Chorismate; Crystal structure; Cystic fibrosis; Inhibition; Mycobacterium abscessus; Non-tuberculous mycobacteria; Salicylate synthase; Siderophores.

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