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New Drugs for the Treatment of Tuberculosis.

ABSTRACT: Tuberculosis (TB) has now surpassed HIV as the leading infectious cause of death, and treatment success rates are declining. Multidrug-resistant TB, extensively drug-resistant TB, and even totally drug-resistant TB threaten to further destabilize disease control efforts. The second wave in TB drug development, which includes the diarylquinoline, bedaquiline, and the nitroimidazoles delamanid and pretomanid, may offer options for simpler, shorter, and potentially all-oral regimens to treat drug-resistant TB. The "third wave" of TB drug development includes numerous promising compounds, including less toxic versions of older drug classes and candidates with novel mechanisms of action.

SUBMITTER: Ignatius EH

PROVIDER: S-EPMC9178517 | biostudies-literature | 2019 Dec

REPOSITORIES: biostudies-literature

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New Drugs for the Treatment of Tuberculosis.

Ignatius Elisa H EH Dooley Kelly E KE

Clinics in chest medicine 20191201 4

Tuberculosis (TB) has now surpassed HIV as the leading infectious cause of death, and treatment success rates are declining. Multidrug-resistant TB, extensively drug-resistant TB, and even totally drug-resistant TB threaten to further destabilize disease control efforts. The second wave in TB drug development, which includes the diarylquinoline, bedaquiline, and the nitroimidazoles delamanid and pretomanid, may offer options for simpler, shorter, and potentially all-oral regimens to treat drug-r ...[more]

PMID: 31731986

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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

New Drugs for the Treatment of Tuberculosis.

Publications

New Drugs for the Treatment of Tuberculosis.

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