GSK2556286 Is a Novel Antitubercular Drug Candidate Effective In Vivo with the Potential To Shorten Tuberculosis Treatment

Eric L. Nuermberger, Maria Santos Martínez-Martínez, Olalla Sanz, Beatriz Urones, Jorge Esquivias, Heena Soni, Rokeya Tasneen, Sandeep Tyagi, Si Yang Li, Paul J. Converse, Helena I. Boshoff, Gregory T. Robertson, Gurdyal S. Besra, Katherine A. Abrahams, Anna M. Upton, Khisimuzi Mdluli, Gary W. Boyle, Sam Turner, Nader Fotouhi, Nicholas C. CammackJuan Miguel Siles, Marta Alonso, Jaime Escribano, Joel Lelievre, Joaquin Rullas-Trincado, Esther Pérez-Herrán, Robert H. Bates, Gareth Maher-Edwards, David Barros, Lluís Ballell, Elena Jiménez

Research output: Contribution to journalArticlepeer-review

Abstract

As a result of a high-throughput compound screening campaign using Mycobacterium tuberculosis-infected macrophages, a new drug candidate for the treatment of tuberculosis has been identified. GSK2556286 inhibits growth within human macrophages (50% inhibitory concentration [IC50] = 0.07 mM), is active against extracellular bacteria in cholesterol-containing culture medium, and exhibits no cross-resistance with known antitubercular drugs. In addition, it has shown efficacy in different mouse models of tuberculosis (TB) and has an adequate safety profile in two preclinical species. These features indicate a compound with a novel mode of action, although still not fully defined, that is effective against both multidrug-resistant (MDR) or extensively drug-resistant (XDR) and drug-sensitive (DS) M. tuberculosis with the potential to shorten the duration of treatment in novel combination drug regimens. (This study has been registered at ClinicalTrials.gov under identifier NCT04472897).

Original languageEnglish (US)
JournalAntimicrobial agents and chemotherapy
Volume66
Issue number6
DOIs
StatePublished - Jun 2022

Keywords

  • KEYWORDS GSK2556286
  • Mycobacterium tuberculosis
  • mouse
  • pharmacology
  • relapse
  • tuberculosis

ASJC Scopus subject areas

  • Pharmacology (medical)
  • Infectious Diseases
  • Pharmacology

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