Intrinsic Antifolate Resistance in <i>Mycobacterium smegmatis</i>
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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. |
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English |
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topic |
Molecular Biology Antifolate resistance Mycobacteria Tuberculosis. |
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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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