%0 Journal Article
%T Discovery of dual-active ethionamide boosters inhibiting the Mycobacterium tuberculosis ESX-1 secretion system.
%A Gries R
%A Chhen J
%A van Gumpel E
%A Theobald SJ
%A Sonnenkalb L
%A Utpatel C
%A Metzen F
%A Koch M
%A Dallenga T
%A Djaout K
%A Baulard A
%A Dal Molin M
%A Rybniker J
%J Cell Chem Biol
%V 31
%N 4
%D 2024 Apr 18
%M 38181799
%F 9.039
%R 10.1016/j.chembiol.2023.12.007
%X 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.