Discovery of dual-active ethionamide boosters inhibiting the Mycobacterium tuberculosis ESX-1 secretion system

Cell Chem Biol. 2024 Apr 18;31(4):699-711.e6. doi: 10.1016/j.chembiol.2023.12.007. Epub 2024 Jan 4.

Abstract

Drug-resistant Mycobacterium tuberculosis (Mtb) remains a major public health concern requiring complementary approaches to standard anti-tuberculous regimens. Anti-virulence molecules or compounds that enhance the activity of antimicrobial prodrugs are promising alternatives to conventional antibiotics. Exploiting host cell-based drug discovery, we identified an oxadiazole compound (S3) that blocks the ESX-1 secretion system, a major virulence factor of Mtb. S3-treated mycobacteria showed impaired intracellular growth and a reduced ability to lyse macrophages. RNA sequencing experiments of drug-exposed bacteria revealed strong upregulation of a distinct set of genes including ethA, encoding a monooxygenase activating the anti-tuberculous prodrug ethionamide. Accordingly, we found a strong ethionamide boosting effect in S3-treated Mtb. Extensive structure-activity relationship experiments revealed that anti-virulence and ethionamide-boosting activity can be uncoupled by chemical modification of the primary hit molecule. To conclude, this series of dual-active oxadiazole compounds targets Mtb via two distinct mechanisms of action.

Keywords: EsxA; EsxB; Mycobacterium tuberculosis; anti-virulence; antibiotic; ethionamide; prodrug; type VII secretion system.

MeSH terms

  • Bacterial Proteins / genetics
  • Ethionamide / pharmacology
  • Humans
  • Mycobacterium tuberculosis*
  • Oxadiazoles / pharmacology
  • Tuberculosis*
  • Type VII Secretion Systems*

Substances

  • Ethionamide
  • Type VII Secretion Systems
  • Oxadiazoles
  • Bacterial Proteins