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New drugs to treat tuberculosis.

ABSTRACT: Tuberculosis (TB) has been a leading cause of death for more than a century. While effective therapies exist, treatment is long and cumbersome. Tuberculosis control is complicated by the overlapping problems created by global inadequacy of public health infrastructures, the interaction of the TB and human immunodeficiency virus epidemics, and the emergence of drug-resistant TB. After a long period of neglect, there is now significant progress in development of TB diagnostics and therapeutics. Focusing on treatment for active TB, we review the new pathways to TB regimen development, and the new and repurposed anti-TB agents in clinical development.

SUBMITTER: Swindells S

PROVIDER: S-EPMC3370665 | biostudies-literature | 2012

REPOSITORIES: biostudies-literature

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New drugs to treat tuberculosis.

Swindells Susan S

F1000 medicine reports 20120601

Tuberculosis (TB) has been a leading cause of death for more than a century. While effective therapies exist, treatment is long and cumbersome. Tuberculosis control is complicated by the overlapping problems created by global inadequacy of public health infrastructures, the interaction of the TB and human immunodeficiency virus epidemics, and the emergence of drug-resistant TB. After a long period of neglect, there is now significant progress in development of TB diagnostics and therapeutics. Fo ...[more]

PMID: 22719795

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Project description: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.

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New drugs to treat tuberculosis.

Publications

New drugs to treat tuberculosis.

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