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

  • Lechartier B Global Health Institute, Ecole Polytechnique Fédérale de Lausanne, Lausanne, Switzerland.
  • Cole ST Global Health Institute, Ecole Polytechnique Fédérale de Lausanne, Lausanne, Switzerland stewart.cole@epfl.ch.
  • 2015-05-20
Published in:
  • Antimicrobial agents and chemotherapy. - 2015
Animals
Antitubercular Agents
Clofazimine
Diarylquinolines
Drug Therapy, Combination
Female
Mice
Mice, Inbred BALB C
Mycobacterium tuberculosis
Piperazines
Thiazines
Tuberculosis, Multidrug-Resistant
Vitamin K 2
English 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 is reduced by NADH dehydrogenase (NDH-2), to release reactive oxygen species upon reoxidation by O2. CZM 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 CZM against M. tuberculosis and found direct competition between CZM and MK-4 for the cidal effect of CZM, against nonreplicating and actively growing bacteria, as MK-4 supplementation blocked the drug's activity against nonreplicating bacteria. We demonstrated that CZM, like bedaquiline, is synergistic in vitro with benzothiazinones such as 2-piperazino-benzothiazinone 169 (PBTZ169), and this synergy also occurs against nonreplicating bacteria. The synergy between CZM and PBTZ169 was lost in an MK-4-rich medium, indicating that MK-4 is the probable link between their activities. The efficacy of the dual combination of CZM 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 CZM in association with PBTZ169 as the basis for a new regimen against drug-resistant strains of M. tuberculosis.
Language
  • English
Open access status
bronze
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Persistent URL
https://sonar.ch/global/documents/69665
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