Cross-Resistance between Clofazimine and Bedaquiline through Upregulation of MmpL5 in Mycobacterium tuberculosis

The antileprosy drug clofazimine is also of interest for the treatment of multidrug-resistant tuberculosis. To understand possible resistance mechanisms, clofazimine-resistant Mycobacterium tuberculosis mutants were isolated in vitro, and, unexpectedly, found to be cross-resistant to bedaquiline. Mutations in the transcriptional regulator Rv0678, with concomitant upregulation of the multisubstrate efflux pump, MmpL5, accounted for this cross-resistance. Mutation in Rv0678 should therefore be considered a confounding factor for the treatment of tuberculosis with clofazimine or bedaquiline. Clofazimine, a riminophenazine, is a standard component ofthe multidrug therapy used for the treatment of leprosy and has contributed to the cure of 16 million patients. In recent years, due to the spread of multidrug-resistant Mycobacterium tubercu-losis strains there has been renewed interest in the use of clofazi-mine for treatment of multidrug-resistant tuberculosis (1). Clo-fazimine has been elegantly demonstrated inM. tuberculosis to be a prodrug, which is reduced by NADH dehydrogenase (Ndh2), and then upon spontaneous reoxidation by O2, to release reactive oxygen species (ROS) (2). As there is no specific target for ROS, resistance to clofazimine is rare and to our knowledge has neve