Mode of Action of Clofazimine and Combination Therapy with Benzothiazinones against Mycobacterium tuberculosis

摘要: Clofazimine (CZM) is an antileprosy drug that was recently repurposed for treatment of multidrug-resistant tuberculosis. In Mycobacterium tuberculosis, CZM appears to act as a prodrug, which reduced by NADH dehydrogenase (NDH-2), release reactive oxygen species upon reoxidation O2. presumably competes with menaquinone (MK-4), key cofactor in the mycobacterial electron transfer chain, its reduction NDH-2. We studied effect MK-4 supplementation on activity against M. tuberculosis and found direct competition between cidal CZM, nonreplicating actively growing bacteria, blocked drug's bacteria. demonstrated like bedaquiline, synergistic vitro benzothiazinones such 2-piperazino-benzothiazinone 169 (PBTZ169), this synergy also occurs The PBTZ169 lost MK-4-rich medium, indicating probable link their activities. efficacy dual combination tested vivo, where great bacterial load obtained murine model chronic Taken together, these data confirm potential association basis new regimen drug-resistant strains