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Insights into the use of cytochrome Bc inhibitors for future therapeutic strategies for tuberculosis

C Aguilar Perez(1) M C Villellas(1) J Guillemont(1) V Gruppo(2) G T Robertson(2) O Turapov(3) S M Glenn(3) G Mukamolova(3) J Dallow(4) H Painter(4) L Brock(5) G Golovkine(5) S Sordello(5) N Lounis(1) J M Gonzalez Moreno(1) V Cox(1) M Crabbe(1) A Lenaerts(2) B Beaten(1) A Pym(1) A Koul(1) L Ballell(1) D Lamprecht(1)

1:Johnson & Johnson Innovative Medicines; 2:Colorado State University; 3:University of Leicester; 4:London School of Hygiene and Tropical Medicine; 5:Evotec

The electron transport chain (ETC) of Mycobacterium tuberculosis is a complex pathway that has driven the attention for druggable targets since the discovery of bedaquiline (BDQ). Other drugs that also act on the ETC, like clofazimine (CFZ) and pyrazinamide (PZA), have demonstrated clinically their value and individual contribution to regimens. Recently, Telacebec (QcrB inhibitor) demonstrated antimycobacterial activity in a Phase II EBA trial. However, information on the contribution of QcrB inhibitors to the sterilizing activity or treatment shortening potential in combination therapy is lacking. In this work we have performed several in vivo studies to prove that combination targeting of the ETC has a strong bactericidal effect with faster killing rates than SOC. Furthermore, we report here for the first time the sterilizing effect of QcrB inhibitors and their contribution to treatment shortening. Lastly, we observe that clinical isolates of Mtb are more susceptible to QcrB inhibition in monotherapy, suggesting that these relapse data (in H37Rv) might be a worse case scenario for the true potential of QcrB containing regimens.

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