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  • Review Article
  • Published:

Drugs versus bugs: in pursuit of the persistent predator Mycobacterium tuberculosis

Nature Reviews Microbiology volume 6, pages 41–52 (2008)Cite this article

Key Points

  • The global tuberculosis (TB) epidemic has not dwindled but has actually grown, largely owing to the challenges that are presented by persistence and resistance. Huge advances in therapeutic regimens are needed to dramatically reduce the course of treatment from months to days.

  • To realize the vulnerabilities of Mycobacterium tuberculosis, genetic methods are being applied to identify genes that are essential to the various metabolic states that are believed to be pertinent to both the establishment and maintenance of infection.

  • The respective essential gene products are being explored using industry-validated drug-discovery methods to produce potential drug candidates. High-throughput virtual and biochemical screening efforts are described, in addition to 'lower-throughput' structure-based designs.

  • Antituberculars in clinical trials are discussed in terms of their respective modes of action and relative strengths and weaknesses as compared with current treatment modalities.

  • A select number of non-TB-approved drugs are described with regard to their potential for being applied as antituberculars. The list includes anti-infectives, such as linezolid and, perhaps surprisingly to some, anti-psychotics, such as the phenothiazine family.

  • Owing to the identification of the gene products that are essential to persistence and their new small-molecule inhibitors, which are fast acting and unencumbered by resistance, scientists may yet be able to realize the lofty goals that have been set for new antitubercular therapies.

Abstract

Tuberculosis (TB) claims a life every 10 seconds and global mortality rates are increasing despite the use of chemotherapy. But why have we not progressed towards the eradication of the disease? There is no simple answer, although apathy, politics, poverty and our inability to fight the chronic infection have all contributed. Drug resistance and HIV-1 are also greatly influencing the current TB battle plans, as our understanding of their complicity grows. In this Review, recent efforts to fight TB will be described, specifically focusing on how drug discovery could combat the resistance and persistence that make TB worthy of the moniker 'The Great White Plague'.

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Figure 1
Figure 2: Overlay of small-molecule inhibitors of InhA.

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Acknowledgements

The authors thank M. Spigelman, R. Goldman, J. Garcia, K. Andries, C. Dukes Hamilton, J. Guilemont, J. Johnson and A. Sternlicht for insightful conversations and, in some cases, providing unpublished results. The authors are supported by a grant from the National Institutes of Health (PO1A1068135) and the Robert A. Welch Foundation.

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Authors and Affiliations

  1. Department of Biochemistry and Biophysics, Texas A&M University, College Station, 77843, Texas, USA

    James C. Sacchettini & Joel S. Freundlich

  2. Department of Immunology and Infectious Diseases, Harvard School of Public Health, Boston, 02115, Massachusetts, USA

    Eric J. Rubin

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  1. James C. Sacchettini
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Correspondence to James C. Sacchettini.

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DATABASES

Entrez Genome Project

Chlamydia pneumoniae

Mycobacterium smegmatis

Mycobacterium tuberculosis

Saccharomyces cerevisiae

Staphylococcus aureus

FURTHER INFORMATION

James C. Sacchettini's homepage

ClinicalTrials.gov

DrugBank

TB Alliance

The Merck Manuals Medical Library

Tuberculosis Antimicrobial Acquisition and Coordinating Facility

Glossary

Pharmacokinetic profile

A quantitative description of the fate of a drug from the moment the treated subject is dosed with the compound to the moment when it (and/or its derivatives) is expelled from the subject.

Pharmacophore

The chemical functional group (or groups) that is present on a molecule and that enables its biological activity.

Chemotype

A chemical functional group or classification of a specific array of functional groups.

Lipinski's rules

A set of delimited physiochemical properties described by C. A. Lipinski that best fit a studied subset of drugs. In general, compounds that adhere to these guidelines are said to be drug-like.

Shikimate pathway

A series of biochemical reactions in plants and microorganisms that are involved in the biosynthesis of aromatic amino acids.

Lead optimization

The process by which a promising small-molecule entity is structurally modified to obtain drug-like pharmacokinetic, pharmacodynamic and safety profiles.

Efflux pump

An active transport system for the removal of toxic molecules, such as antibiotics, from cells.

Structure–activity relationship

(SAR). The relationship between the chemical structure of a compound and its biological or pharmacological activity. This type of relationship can be assessed by considering a series of molecules, each with a slightly different structure, and then noting the effect on the biological activity that is associated with each structural variation.

Fast-track status

The FDA status that is reserved for products that demonstrate the potential to treat a serious or life-threatening condition.

F0 subunit of atp synthase

The transmembrane portion of the enzyme complex that is involved in the biosynthesis of ATP, which has a role in the passage of protons through the membrane.

Ames mutagenicity test

A sensitive biological method for measuring the mutagenic potency of chemical substances.

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Sacchettini, J., Rubin, E. & Freundlich, J. Drugs versus bugs: in pursuit of the persistent predator Mycobacterium tuberculosis. Nat Rev Microbiol 6, 41–52 (2008). https://doi.org/10.1038/nrmicro1816

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