Clofazimine (CFM) is an anti-leprosy drug that was recently repurposed for treatment of multidrug-resistant tuberculosis. In Mycobacterium tuberculosis, CFM appears to act as a pro-drug, which is reduced by NADH dehydrogenase (NDH-2), to release reactive oxygen species upon re-oxidation by O2. CFM presumably competes with menaquinone (MK-4), a key cofactor in the mycobacterial electron transfer chain, for its reduction by NDH-2. We studied the effect of MK-4 supplementation on the activity of CFM against M. tuberculosis and found direct competition between CFM and MK-4 for the cidal effect of CFM, both against non-replicating and actively growing bacteria, as MK-4 supplementation blocked the drug's activity against non-replicating bacteria. We demonstrated that CFM, like bedaquiline, is synergistic in vitro with benzothiazinones such as PBTZ169, and this synergy also occurs against non-replicating bacteria. The synergy between CFM and PBTZ169 was lost in a MK-4-rich medium, indicating that MK-4 is the probable link between their activities. The efficacy of the dual combination CFM and PBTZ169 was tested in vivo where a great reduction in bacterial load was obtained in a murine model of chronic tuberculosis. Taken together, these data confirm the potential of CFM, in association with PBTZ169, as the basis for a new regimen against drug-resistant strains of M. tuberculosis.
BT - Antimicrobial agents and chemotherapy C1 -http://www.ncbi.nlm.nih.gov/pubmed/25987624?dopt=Abstract
DO - 10.1128/AAC.00395-15 J2 - Antimicrob. Agents Chemother. LA - eng N2 -Clofazimine (CFM) is an anti-leprosy drug that was recently repurposed for treatment of multidrug-resistant tuberculosis. In Mycobacterium tuberculosis, CFM appears to act as a pro-drug, which is reduced by NADH dehydrogenase (NDH-2), to release reactive oxygen species upon re-oxidation by O2. CFM presumably competes with menaquinone (MK-4), a key cofactor in the mycobacterial electron transfer chain, for its reduction by NDH-2. We studied the effect of MK-4 supplementation on the activity of CFM against M. tuberculosis and found direct competition between CFM and MK-4 for the cidal effect of CFM, both against non-replicating and actively growing bacteria, as MK-4 supplementation blocked the drug's activity against non-replicating bacteria. We demonstrated that CFM, like bedaquiline, is synergistic in vitro with benzothiazinones such as PBTZ169, and this synergy also occurs against non-replicating bacteria. The synergy between CFM and PBTZ169 was lost in a MK-4-rich medium, indicating that MK-4 is the probable link between their activities. The efficacy of the dual combination CFM and PBTZ169 was tested in vivo where a great reduction in bacterial load was obtained in a murine model of chronic tuberculosis. Taken together, these data confirm the potential of CFM, in association with PBTZ169, as the basis for a new regimen against drug-resistant strains of M. tuberculosis.
PY - 2015 T2 - Antimicrobial agents and chemotherapy TI - Insight into the mode of action of clofazimine and combination therapy with benzothiazinones against Mycobacterium tuberculosis. SN - 1098-6596 ER -