Bactericidal and sterilizing activity of novel regimens combining bedaquiline or TBAJ-587 with GSK2556286 and TBA-7371 in a mouse model of tuberculosis

Si Yang Li, Sandeep Tyagi, Heena Soni, Fabrice Betoudji, Paul J. Converse, Khisimuzi Mdluli, Anna M. Upton, Nader Fotouhi, David Barros-Aguirre, Lluís Ballell, Elena Jimenez-Navarro, Eric L. Nuermberger

Research output: Contribution to journalArticlepeer-review

Abstract

The combination of bedaquiline, pretomanid, and linezolid (BPaL) has become a preferred regimen for treating multidrug- and extensively drug-resistant tuberculosis (TB). However, treatment-limiting toxicities of linezolid and reports of emerging bedaquiline and pretomanid resistance necessitate efforts to develop new short-course oral regimens. We recently found that the addition of GSK2556286 increases the bactericidal and sterilizing activity of BPa-containing regimens in a well-established BALB/c mouse model of tuberculosis. Here, we used this model to evaluate the potential of new regimens combining bedaquiline or the more potent diarylquinoline TBAJ-587 with GSK2556286 and the DprE1 inhibitor TBA-7371, all of which are currently in early-phase clinical trials. We found the combination of bedaquiline, GSK2556286, and TBA-7371 to be more active than the first-line regimen and nearly as effective as BPaL in terms of bactericidal and sterilizing activity. In addition, we found that GSK2556286 and TBA-7371 were as effective as pretomanid and the novel oxazolidinone TBI-223 when either drug pair was combined with TBAJ-587 and that the addition of GSK2556286 increased the bactericidal activity of the TBAJ-587, pretomanid, and TBI-223 combination. We conclude that GSK2556286 and TBA-7371 have the potential to replace pretomanid, an oxazolidinone, or both components, in combination with bedaquiline or TBAJ-587.

Original languageEnglish (US)
JournalAntimicrobial agents and chemotherapy
Volume68
Issue number4
DOIs
StatePublished - Apr 2024

Keywords

  • GSK2556286
  • Mycobacterium tuberculosis
  • TBA-7371
  • TBAJ-587
  • TBI-223
  • bedaquiline
  • linezolid
  • mouse model
  • pretomanid
  • tuberculosis

ASJC Scopus subject areas

  • Pharmacology (medical)
  • Infectious Diseases
  • Pharmacology

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