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Intrinsic Antifolate Resistance in Mycobacterium smegmatis

Ogwang, Sam
http://rave.ohiolink.edu/etdc/view?acc_num=case1270147885

Abstract Details

2010, Master of Sciences, Case Western Reserve University, Pathology.
The genus Mycobacterium contains species responsible for two deadly human diseases: leprosy and tuberculosis. Chemotherapeutic agents enable treatment of mycobacterial diseases but are fraught with drug resistance. Folate antagonists (antifolates) inhibit microbial growth by creating intracellular folate deficiency through blockage of de novo folate synthesis. Antifolate resistance is due to mutations altering the structure or expression of enzymes targeted by these drugs. To understand antifolate intrinsic resistance, we created a library of 13000 M. smegmatis transposon mutants. 31 mutants, hypersusceptible to antifolates, had disruptions in genes related to folate metabolism. We characterized one with a mutation in msmeg_5472 (fueL), encoding 5,10-methenyltetrahydrofolate synthetase that converts the metabolically inert 5-formyltetrahrofolate (folinic acid) to 5,10-methenyltetrahydrofolate, utilized in one–carbon metabolism. Genetic, microbiological and biochemical tests suggested that folinic acid is an alternate folate source that allows mycobacteria to circumvent blockage of de novo folate sythesis. fueL is a determinant of intrinsic antifolate resistance.
James Anderson, MD, PhD (Committee Chair)
Henry Boom, MD (Committee Member)
Liem Nguyen, PhD (Advisor)
68 p.
Molecular Biology
Antifolate resistance; Mycobacteria; Tuberculosis.

Recommended Citations

Citations

  • Ogwang, S. (2010). Intrinsic Antifolate Resistance in Mycobacterium smegmatis [Master's thesis, Case Western Reserve University]. OhioLINK Electronic Theses and Dissertations Center. http://rave.ohiolink.edu/etdc/view?acc_num=case1270147885

    APA Style (7th edition)

  • Ogwang, Sam. Intrinsic Antifolate Resistance in Mycobacterium smegmatis. 2010. Case Western Reserve University, Master's thesis. OhioLINK Electronic Theses and Dissertations Center, http://rave.ohiolink.edu/etdc/view?acc_num=case1270147885.

    MLA Style (8th edition)

  • Ogwang, Sam. "Intrinsic Antifolate Resistance in Mycobacterium smegmatis." Master's thesis, Case Western Reserve University, 2010. http://rave.ohiolink.edu/etdc/view?acc_num=case1270147885

    Chicago Manual of Style (17th edition)

case1270147885
592
© 2010, all rights reserved.
This open access ETD is published by Case Western Reserve University School of Graduate Studies and OhioLINK.