A bactericidal tuberculosis drug regimen driven by inhibition of the terminal oxidases by pretomanid

Abstract Pretomanid is a unique anti-tuberculosis agent that inhibits both cell-wall synthesis and bioenergetics in Mycobacterium tuberculosis . While targeting the cell wall triggers a rapid bactericidal effect on replicating mycobacteria, the release of nitric oxide is linked to bactericidal potency against antibiotic-tolerant, non-replicating subpopulations through interference with the electron transport chain. Nonetheless, the specific molecular target(s) of the drug remain unknown. Through the utilization of genetic and chemical biology approaches, we present evidence that pretomanid inhibits both the cytochrome bcc:aa 3 and bd oxidase respiratory branches. This property leads to a pronounced synergy with telacebec (Q203), a clinical-stage drug targeting the cytochrome bcc:aa 3 , while concurrently curtailing the emergence of resistance to pretomanid. Furthermore, the incorporation of the cytochrome bd oxidase inhibitor ND-011992 resulted in a triple drug combination highly bactericidal against antibiotic-tolerant, non-replicating as well as replicating M. tuberculosis . The combination of pretomanid and drugs targeting the terminal oxidases holds the potential to serve as the cornerstone for an efficacious sterilizing drug regimen against tuberculosis.