title: The folate pathway is a target for resistance to the drug para-aminosalicylic acid (PAS) in mycobacteria.
abstract: The increasing rate of multidrug-resistant tuberculosis has led to more use of second-line antibiotics such as para-aminosalicylic acid (PAS). The mode of action of PAS remains unclear, and mechanisms of resistance to this drug are undefined. We have isolated PAS-resistant transposon mutants of Mycobacterium bovis BCG with insertions in the thymidylate synthase (thyA) gene, a critical determinant of intracellular folate levels. BCG thyA mutants have reduced thymidylate synthase activity and are resistant to known inhibitors of the folate pathway. We also find that mutations in thyA are associated with clinical PAS resistance. We have identified PAS-resistant Mycobacterium tuberculosis isolates from infected patients, which harbour mutations in thyA and show reduced activity of the encoded enzyme. Thus, PAS acts in the folate pathway, and thyA mutations probably represent a mechanism of developing resistance not only to PAS but also to other drugs that target folate metabolism.
authors.affiliation: Department of Immunology and Infectious Diseases, Harvard School of Public Health, Boston, MA 02115, USA.
authors.forename: Jyothi
authors.initials: J
authors.lastname: Rengarajan
authors.forename: Christopher M
authors.initials: CM
authors.lastname: Sassetti
authors.forename: Vera
authors.initials: V
authors.lastname: Naroditskaya
authors.forename: Alexander
authors.initials: A
authors.lastname: Sloutsky
authors.forename: Barry R
authors.initials: BR
authors.lastname: Bloom
authors.forename: Eric J
authors.initials: EJ
authors.lastname: Rubin
mesh_terms: D010131:Aminosalicylic Acid / Q000008:administration & dosage / Q000097:blood / Q000494:pharmacology*; D024881:Drug Resistance, Bacterial / Q000235:genetics*; D018432:Drug Resistance, Multiple / Q000235:genetics*; D005492:Folic Acid / Q000378:metabolism*; D005493:Folic Acid Antagonists; D008826:Microbial Sensitivity Tests; D009154:Mutation; D009169:Mycobacterium tuberculosis / Q000187:drug effects* / Q000235:genetics; D018088:Tuberculosis, Multidrug-Resistant / Q000382:microbiology
chemical_list: D005493:Folic Acid Antagonists; D010131:Aminosalicylic Acid; D005492:Folic Acid