Intrinsic Antifolate Resistance in <i>Mycobacterium smegmatis</i>

Intrinsic Antifolate Resistance in <i>Mycobacterium smegmatis</i>

Bibliographic Details
Main Author: Ogwang, Sam
Language:English
Published: Case Western Reserve University School of Graduate Studies / OhioLINK 2010
Subjects:
Molecular Biology
Antifolate resistance
Mycobacteria
Tuberculosis.
Online Access:http://rave.ohiolink.edu/etdc/view?acc_num=case1270147885
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spelling ndltd-OhioLink-oai-etd.ohiolink.edu-case12701478852021-08-03T05:33:33Z Intrinsic Antifolate Resistance in <i>Mycobacterium smegmatis</i> Ogwang, Sam Molecular Biology Antifolate resistance Mycobacteria Tuberculosis. The genus <i>Mycobacterium</i> 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 <i>de novo</i> 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 <i>msmeg_5472</i> (<i>fueL</i>), 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. <i>fueL</i> is a determinant of intrinsic antifolate resistance. 2010-07-06 English text Case Western Reserve University School of Graduate Studies / OhioLINK http://rave.ohiolink.edu/etdc/view?acc_num=case1270147885 http://rave.ohiolink.edu/etdc/view?acc_num=case1270147885 unrestricted This thesis or dissertation is protected by copyright: all rights reserved. It may not be copied or redistributed beyond the terms of applicable copyright laws.
collection NDLTD
language English
sources NDLTD
topic Molecular Biology
Antifolate resistance
Mycobacteria
Tuberculosis.
spellingShingle Molecular Biology
Antifolate resistance
Mycobacteria
Tuberculosis.
Ogwang, Sam
Intrinsic Antifolate Resistance in <i>Mycobacterium smegmatis</i>
author Ogwang, Sam
author_facet Ogwang, Sam
author_sort Ogwang, Sam
title Intrinsic Antifolate Resistance in <i>Mycobacterium smegmatis</i>
title_short Intrinsic Antifolate Resistance in <i>Mycobacterium smegmatis</i>
title_full Intrinsic Antifolate Resistance in <i>Mycobacterium smegmatis</i>
title_fullStr Intrinsic Antifolate Resistance in <i>Mycobacterium smegmatis</i>
title_full_unstemmed Intrinsic Antifolate Resistance in <i>Mycobacterium smegmatis</i>
title_sort intrinsic antifolate resistance in <i>mycobacterium smegmatis</i>
publisher Case Western Reserve University School of Graduate Studies / OhioLINK
publishDate 2010
url http://rave.ohiolink.edu/etdc/view?acc_num=case1270147885
work_keys_str_mv AT ogwangsam intrinsicantifolateresistanceinimycobacteriumsmegmatisi
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