Nanoenabling MbtI Inhibitors for Next-Generation Tuberculosis Therapy

Giulia Cazzaniga; Matteo Mori; Anna Griego; Edoardo Scarpa; Giorgia Moschetti; Stefano Muzzioli; Giovanni Stelitano; Laurent R. Chiarelli; Mario Cocorullo; Emanuele Casali; Alessio Porta; Giuseppe Zanoni; Andrea Tresoldi; Elena Pini; Íris L. Batalha; Giuseppe Battaglia; Tiziano Tuccinardi; Loris Rizzello; Stefania Villa; Fiorella Meneghetti

doi:10.1021/acs.jmedchem.4c02386

Nanoenabling MbtI Inhibitors for Next-Generation Tuberculosis Therapy

Giulia Cazzaniga, Matteo Mori, Anna Griego, Edoardo Scarpa, Giorgia Moschetti, Stefano Muzzioli, Giovanni Stelitano, Laurent R. Chiarelli, Mario Cocorullo, Emanuele Casali, Alessio Porta, Giuseppe Zanoni, Andrea Tresoldi, Elena Pini, Íris L. Batalha, Giuseppe Battaglia, Tiziano Tuccinardi, Loris Rizzello, Stefania Villa, Fiorella Meneghetti

Department of Life Sciences

Research output: Contribution to journal › Article › peer-review

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.

Original language	English
Pages (from-to)	5312-5332
Number of pages	21
Journal	Journal of Medicinal Chemistry
Volume	68
Issue number	5
Early online date	3 Mar 2025
DOIs	https://doi.org/10.1021/acs.jmedchem.4c02386
Publication status	Published - 13 Mar 2025

Acknowledgements

M.M., E.P., and S.V. thank Camilla Bismuth and Diego Degli Agosti for their valuable contributions to this work.

Funding

M.M., E.P., and S.V. thank Camilla Bismuth and Diego Degli Agosti for their valuable contributions to this work.

ASJC Scopus subject areas

Molecular Medicine
Drug Discovery

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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Cite this

Cazzaniga, G., Mori, M., Griego, A., Scarpa, E., Moschetti, G., Muzzioli, S., Stelitano, G., Chiarelli, L. R., Cocorullo, M., Casali, E., Porta, A., Zanoni, G., Tresoldi, A., Pini, E., Batalha, Í. L., Battaglia, G., Tuccinardi, T., Rizzello, L., Villa, S., & Meneghetti, F. (2025). Nanoenabling MbtI Inhibitors for Next-Generation Tuberculosis Therapy. Journal of Medicinal Chemistry, 68(5), 5312-5332. https://doi.org/10.1021/acs.jmedchem.4c02386

Cazzaniga, G, Mori, M, Griego, A, Scarpa, E, Moschetti, G, Muzzioli, S, Stelitano, G, Chiarelli, LR, Cocorullo, M, Casali, E, Porta, A, Zanoni, G, Tresoldi, A, Pini, E, Batalha, ÍL, Battaglia, G, Tuccinardi, T, Rizzello, L, Villa, S & Meneghetti, F 2025, 'Nanoenabling MbtI Inhibitors for Next-Generation Tuberculosis Therapy', Journal of Medicinal Chemistry, vol. 68, no. 5, pp. 5312-5332. https://doi.org/10.1021/acs.jmedchem.4c02386

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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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AU - Muzzioli, Stefano

AU - Stelitano, Giovanni

AU - Chiarelli, Laurent R.

AU - Cocorullo, Mario

AU - Casali, Emanuele

AU - Porta, Alessio

AU - Zanoni, Giuseppe

AU - Tresoldi, Andrea

AU - Pini, Elena

AU - Batalha, Íris L.

AU - Battaglia, Giuseppe

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AU - Rizzello, Loris

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Nanoenabling MbtI Inhibitors for Next-Generation Tuberculosis Therapy

Abstract

Acknowledgements

Funding

ASJC Scopus subject areas

UN SDGs

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