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

Molecular Microbiology
Jyothi RengarajanE J Rubin

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.

References

Feb 1, 1995·Antimicrobial Agents and Chemotherapy·P HuovinenO Sköld
Feb 7, 1998·Infection and Immunity·A CersiniM L Bernardini
Oct 19, 2001·Proceedings of the National Academy of Sciences of the United States of America·C M SassettiE J Rubin
Mar 16, 2002·Science·Christopher DyeMario C Raviglione
May 25, 2002·Science·Hannu MyllykallioUrsula Liebl
Jan 10, 2003·The New England Journal of Medicine·Carole MitnickPaul Farmer
Mar 27, 2003·Molecular Microbiology·Christopher M SassettiEric J Rubin

❮ Previous
Next ❯

Citations

Oct 17, 2006·Clinical Microbiology Reviews·Barun MathemaBarry N Kreiswirth
Sep 25, 2007·Journal of Bacteriology·Damien LeducHannu Myllykallio
May 12, 2011·The Journal of Antimicrobial Chemotherapy·Pedro Eduardo Almeida Almeida Da Silva, Juan Carlos Palomino
Mar 17, 2012·European Journal of Medicinal Chemistry·Baptiste VillemagneNicolas Willand
Aug 27, 2010·Tuberculosis·Joel S FreundlichJames C Sacchettini
Jun 23, 2007·Tuberculosis·Sang-Nae Cho, Patrick J Brennan
Jul 14, 2007·Tuberculosis·Christopher R E McEvoyRobin M Warren
Apr 14, 2016·Future Microbiology·Juan Carlos Palomino, Anandi Martin
Apr 16, 2016·Microbial Drug Resistance : MDR : Mechanisms, Epidemiology, and Disease·Vincent Wing-Sang ChengStephen Kwok-Wing Tsui
Feb 16, 2006·Drug Discovery Today·Ying ZhangSteven Denkin
Apr 1, 2015·Future Medicinal Chemistry·Valentina Ferrari, Michaela Serpi
Feb 25, 2006·Cell·David M RaskinJohn J Mekalanos
May 11, 2016·Archives of Toxicology·Liem Nguyen
May 25, 2016·Biochimica Et Biophysica Acta. General Subjects·Kinga Nyíri, Beáta G Vértessy
Jul 29, 2015·Scientific Reports·Tanmoy RoychowdhuryAlok Bhattacharya
Jan 21, 2017·Euro Surveillance : Bulletin Européen Sur Les Maladies Transmissibles = European Communicable Disease Bulletin·Lena FiebigWalter Haas
Dec 29, 2016·Archives of Pharmacal Research·Hajjaj H M Abdu-AllahDharmarajan Sriram
Mar 5, 2011·The Journal of Biological Chemistry·Sam OgwangLiem Nguyen
Mar 8, 2007·Nature Medicine·Christopher M Sassetti, Eric J Rubin
Dec 15, 2007·Nature Reviews. Microbiology·James C SacchettiniJoel S Freundlich
Dec 13, 2006·Nature Reviews. Drug Discovery·Lynn L Silver
Oct 31, 2012·Expert Review of Anti-infective Therapy·Kerstin A Wolff, Liem Nguyen
Jun 20, 2013·The Journal of Biological Chemistry·Jun ZhengLuis R Camacho

❮ Previous
Next ❯

Related Concepts

Related Feeds

Antifungals

An antifungal, also known as an antimycotic medication, is a pharmaceutical fungicide or fungistatic used to treat and prevent mycosis such as athlete's foot, ringworm, candidiasis, cryptococcal meningitis, and others. Discover the latest research on antifungals here.

Antimicrobial Resistance (ASM)

Antimicrobial resistance poses a significant threat to the continued successful use of antimicrobial agents for the treatment of bacterial infections.

Bacterial Respiration

This feed focuses on cellular respiration in bacteria, known as bacterial respiration. Discover the latest research here.

Antimicrobial Resistance

Antimicrobial resistance poses a significant threat to the continued successful use of antimicrobial agents for the treatment of bacterial infections.

Antifungals (ASM)

An antifungal, also known as an antimycotic medication, is a pharmaceutical fungicide or fungistatic used to treat and prevent mycosis such as athlete's foot, ringworm, candidiasis, cryptococcal meningitis, and others. Discover the latest research on antifungals here.

Related Papers

Proceedings of the National Academy of Sciences of the United States of America
C M Sassetti, E J Rubin
Proceedings of the National Academy of Sciences of the United States of America
C M SassettiE J Rubin
© 2022 Meta ULC. All rights reserved