title: 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.affiliation: Department of Microbiology, Center for Infectious Diseases and Microbiology Translational Research, University of Minnesota Medical School, Minneapolis, Minnesota, USA.
authors.forename: Yusuke
authors.initials: Y
authors.lastname: Minato
authors.affiliation: Department of Microbiology, Center for Infectious Diseases and Microbiology Translational Research, University of Minnesota Medical School, Minneapolis, Minnesota, USA.
authors.forename: Joshua M
authors.initials: JM
authors.lastname: Thiede
authors.affiliation: Department of Microbiology, Center for Infectious Diseases and Microbiology Translational Research, University of Minnesota Medical School, Minneapolis, Minnesota, USA.
authors.forename: Shannon Lynn
authors.initials: SL
authors.lastname: Kordus
authors.affiliation: Department of Chemistry, Harvard University, Cambridge, Massachusetts, USA.
authors.forename: Edward J
authors.initials: EJ
authors.lastname: McKlveen
authors.affiliation: Department of Microbiology, Center for Infectious Diseases and Microbiology Translational Research, University of Minnesota Medical School, Minneapolis, Minnesota, USA.
authors.forename: Breanna J
authors.initials: BJ
authors.lastname: Turman
authors.affiliation: Department of Microbiology, Center for Infectious Diseases and Microbiology Translational Research, University of Minnesota Medical School, Minneapolis, Minnesota, USA abaughn@umn.edu.
authors.forename: Anthony D
authors.initials: AD
authors.lastname: Baughn
mesh_terms: D010131:Aminosalicylic Acid / Q000494:pharmacology*; D000995:Antitubercular Agents / Q000494:pharmacology*; D005492:Folic Acid / Q000378:metabolism*; D008826:Microbial Sensitivity Tests; D009169:Mycobacterium tuberculosis / Q000187:drug effects* / Q000378:metabolism*; D018088:Tuberculosis, Multidrug-Resistant
chemical_list: D000995:Antitubercular Agents; D010131:Aminosalicylic Acid; D005492:Folic Acid