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The chemical biology of new drugs in the development for tuberculosis.

ABSTRACT: With the worldwide emergence of multidrug-resistant (MDR) and extensively drug-resistant (XDR) strains of Mycobacterium tuberculosis (Mtb), there are serious concerns about the continued ability to contain this disease. We discuss the most promising new drugs in late-stage development that might be useful in treating MDR and XDR forms of the disease. These agents have novel mechanisms of action that are not targeted by the standard drugs used presently to treat susceptible strains.

SUBMITTER: Barry CE

PROVIDER: S-EPMC2918717 | biostudies-literature | 2010 Aug

REPOSITORIES: biostudies-literature

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The chemical biology of new drugs in the development for tuberculosis.

Barry Clifton E CE Blanchard John S JS

Current opinion in chemical biology 20100507 4

With the worldwide emergence of multidrug-resistant (MDR) and extensively drug-resistant (XDR) strains of Mycobacterium tuberculosis (Mtb), there are serious concerns about the continued ability to contain this disease. We discuss the most promising new drugs in late-stage development that might be useful in treating MDR and XDR forms of the disease. These agents have novel mechanisms of action that are not targeted by the standard drugs used presently to treat susceptible strains. ...[more]

PMID: 20452813

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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.

Dataset Information

The chemical biology of new drugs in the development for tuberculosis.

Publications

The chemical biology of new drugs in the development for tuberculosis.

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