The folate pathway is a target for resistance to the drug para‐aminosalicylic acid (PAS) in mycobacteria

• Published in: Molecular microbiology Vol. 53; no. 1; pp. 275 - 282
• Main Authors: Rengarajan, Jyothi, Sassetti, Christopher M., Naroditskaya, Vera, Sloutsky, Alexander, Bloom, Barry R., Rubin, Eric J.
• Format: Journal Article
• Language: English
• Published: Oxford, UK Blackwell Science Ltd 01.07.2004; Blackwell Science; Blackwell Publishing Ltd
• Subjects: Aminosalicylic Acid - administration & dosage; Aminosalicylic Acid - blood; Aminosalicylic Acid - pharmacology; Biological and medical sciences; Drug Resistance, Bacterial - genetics; Drug Resistance, Multiple - genetics; Folic Acid - metabolism; Folic Acid Antagonists; Fundamental and applied biological sciences. Psychology; Microbial Sensitivity Tests; Microbiology; Mutation; Mycobacterium bovis; Mycobacterium tuberculosis; Mycobacterium tuberculosis - drug effects; Mycobacterium tuberculosis - genetics; Tuberculosis, Multidrug-Resistant - microbiology; Resistance; Mycobacterium; Microbiology; Mycobacteriales; Mycobacteriaceae; Bacteria; Aminosalicylic acid; Actinomycetes; Antituberculous agent; Antibacterial agent; Folate
• ISSN: 0950-382X; 1365-2958
• DOI: 10.1111/j.1365-2958.2004.04120.x

Summary 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.