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
  • 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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