Mycobacterium tuberculosis folate metabolism and the mechanistic basis for para-aminosalicylic acid susceptibility and resistance.

Abstract

para-Aminosalicylic acid (PAS) entered clinical use in 1946 as the second exclusive drug for the treatment of tuberculosis (TB). While PAS was initially a first-line TB drug, the introduction of more potent antitubercular agents relegated PAS to the second-line tier of agents used for the treatment of drug-resistant Mycobacterium tuberculosis infections. Despite the long history of PAS usage, an understanding of the molecular and biochemical mechanisms governing the susceptibility and resistance of M. tuberculosis to this drug has lagged behind that of most other TB drugs. Herein, we discuss previous studies that demonstrate PAS-mediated disruption of iron acquisition, as well as recent genetic, biochemical, and metabolomic studies that have revealed that PAS is a prodrug that ultimately corrupts one-carbon metabolism through inhibition of the formation of reduced folate species. We also discuss findings from laboratory and clinical isolates that link alterations in folate metabolism to PAS resistance. These advancements in our understanding of the basis of the susceptibility and resistance of M. tuberculosis to PAS will enable the development of novel strategies to revitalize this and other antimicrobial agents for use in the global effort to eradicate TB.

• Authors: Yusuke Minato, Joshua M Thiede, Shannon Lynn Kordus, Edward J McKlveen, Breanna J Turman, Anthony D Baughn
• Journal: Antimicrobial agents and chemotherapy (Antimicrob Agents Chemother) Vol. 59 Issue 9 Pg. 5097-106 (Sep 2015) ISSN: 1098-6596 [Electronic] United States
• PMID: 26033719 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't, Review)
• Copyright: Copyright © 2015, American Society for Microbiology. All Rights Reserved.

Chemical References

• Antitubercular Agents
• Aminosalicylic Acid
• Folic Acid

Topics

• Aminosalicylic Acid (pharmacology)
• Antitubercular Agents (pharmacology)
• Folic Acid (metabolism)
• Microbial Sensitivity Tests
• Mycobacterium tuberculosis (drug effects, metabolism)
• Tuberculosis, Multidrug-Resistant