2. Academic Validation
  3. Nanoenabling MbtI Inhibitors for Next-Generation Tuberculosis Therapy

Nanoenabling MbtI Inhibitors for Next-Generation Tuberculosis Therapy

  • J Med Chem. 2025 Mar 13;68(5):5312-5332. doi: 10.1021/acs.jmedchem.4c02386.
Giulia Cazzaniga 1 2,  Matteo Mori 1,  Anna Griego 1 3,  Edoardo Scarpa 1 3,  Giorgia Moschetti 1 3,  Stefano Muzzioli 1 3,  Giovanni Stelitano 4,  Laurent R Chiarelli 4,  Mario Cocorullo 4,  Emanuele Casali 5,  Alessio Porta 5,  Giuseppe Zanoni 5,  Andrea Tresoldi 1,  Elena Pini 1,  Íris L Batalha 6,  Giuseppe Battaglia 7 8,  Tiziano Tuccinardi 9,  Loris Rizzello 1 3,  Stefania Villa 1,  Fiorella Meneghetti 1
Affiliations

Affiliations

  • 1 Department of Pharmaceutical Sciences, University of Milan, Via L. Mangiagalli 25, 20133 Milano, Italy.
  • 2 Department of Science and High Technology, University of Insubria, via Valleggio 9, 22100 Como, Italy.
  • 3 National Institute of Molecular Genetic (INGM), Via F. Sforza 35, 20122 Milano, Italy.
  • 4 Department of Biology and Biotechnology "Lazzaro Spallanzani″, University of Pavia, via A. Ferrata 9, 27100 Pavia, Italy.
  • 5 Department of Chemistry, University of Pavia, Viale T. Taramelli 12, 27100 Pavia, Italy.
  • 6 Department of Life Sciences, University of Bath, Claverton Down, BA2 7AY Bath, U.K.
  • 7 Molecular Bionics Group, Institute for Bioengineering of Catalonia (IBEC), C. Baldiri Reixac 10-12, 08028 Barcelona, Spain.
  • 8 Catalan Institution of Research and Advanced Studies, (ICREA), Passeig de Lluís Companys, 23, 08010 Barcelona, Spain.
  • 9 Department of Pharmacy, University of Pisa, Via Bonanno Pisano 6, 56126 Pisa, Italy.
PMID: 40029993 DOI: 10.1021/acs.jmedchem.4c02386
Abstract

The urgent need for safer and innovative antitubercular agents remains a priority for the scientific community. In pursuit of this goal, we designed and evaluated novel 5-phenylfuran-2-carboxylic acid derivatives targeting Mycobacterium tuberculosis (Mtb) salicylate synthase (MbtI), a key Enzyme, absent in humans, that plays a crucial role in Mtb virulence. Several potent MbtI inhibitors demonstrating significant antitubercular activity and a favorable safety profile were identified. Structure-guided optimization yielded 5-(3-cyano-5-isobutoxyphenyl)furan-2-carboxylic acid (1e), which exhibited strong MbtI inhibition (IC50 = 11.2 μM) and a promising in vitro antitubercular activity (MIC99 = 32 μM against M. bovis BCG). Esters of 1e were effectively loaded into poly(2-methacryloyloxyethyl phosphorylcholine)-poly(2-(diisopropylamino)ethyl methacrylate) (PMPC-PDPA) polymersomes (POs) and delivered to intracellular mycobacteria, resulting in reduced Mtb viability. This study provides a foundation for the use of POs in the development of future MbtI-targeted therapies for tuberculosis.

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