Mycobacterium tuberculosis develops spontaneous resistance mutants to virtually 
every drug in use. Courses of therapy select for these mutants and 
drug-resistant organisms emerge. The development of drug-resistant organisms has 
reached the point that drug resistance now threatens to undermine global success 
against tuberculosis (TB). New drugs are needed. The last new class of drugs 
specifically developed for treatment of TB was the rifamycins over 40 years ago. 
New funding sources and the development of product development partnerships have 
energized the TB drug development effort. There are now more TB drugs in 
development than at any time in the past. The first of these drugs to be 
developed and marketed was bedaquiline. Bedaquiline has an entirely novel 
mechanism of action and so should be active against otherwise highly resistant 
organisms. It acts on the transmembrane component of adenosine triphosphate 
synthase and acts by preventing electron transport. This raises the exciting 
possibility that bedaquiline may be active against less metabolically active 
organisms. Drug-drug interactions between rifamycins and the cytochrome P450-3A 
system will limit bedaquiline's utility and create complexity in treatment 
regimens. In clinical trials, treatment with bedaquiline added to a background 
multidrug-resistant TB regimen was associated with earlier culture conversion 
and higher cure rates, but there were unexplained excess deaths in the 
bedaquiline arms of these trials. Food and Drug Administration approved 
bedaquiline for the treatment of multidrug-resistant TB when an effective 
treatment regimen cannot otherwise be provided. They required a black box 
warning about excess deaths and require that a phase III trial be completed. A 
planned Phase III trial is being reorganized. While bedaquiline is an exciting 
drug and marks a dramatic moment in the history of TB treatment, its ultimate 
place in the anti-TB drug armamentarium is unclear pending the Phase III trial 
and the development of other new drugs that are in the pipeline.