Terminal oxidases as potential drug targets in mycobacteria

The main problem about tuberculosis treatment is the persistence of Mycobacterium tuberculosis despite prolonged chemotherapy. Hence, there is an urgent need to discover new drug targets to combat the dormant MDR/XDR bacilli. Nutrient-starvation triggers growth termination and renders them phenotypi...

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Main Author: Foo, Joan Yuan Zhen
Other Authors: Kevin Pethe
Format: Final Year Project
Language:English
Published: 2016
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Online Access:http://hdl.handle.net/10356/68930
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Institution: Nanyang Technological University
Language: English
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spelling sg-ntu-dr.10356-689302023-02-28T18:02:35Z Terminal oxidases as potential drug targets in mycobacteria Foo, Joan Yuan Zhen Kevin Pethe School of Biological Sciences DRNTU::Science The main problem about tuberculosis treatment is the persistence of Mycobacterium tuberculosis despite prolonged chemotherapy. Hence, there is an urgent need to discover new drug targets to combat the dormant MDR/XDR bacilli. Nutrient-starvation triggers growth termination and renders them phenotypically drug-resistant. We conducted a series of experiments to study the feasibility of terminal oxidases i.e. cytochrome bd oxidase and cytochrome bc1-aa3 complex as potential drug targets in nutrient-starved mycobacteria by investigating the differences in energy metabolism, cell viability and drug susceptibility in nutrient-starved BCG ∆bd as compared to BCG WT and BCG ∆bd-pMV306-bd when treated with Q203, bedaquiline and INH. We concluded that combination of specific inhibitor of cytochrome bd oxidase with Q203 could have multiplicative effect against log-phase growing and dormant mycobacteria. Furthermore, potency of Q203 on nutrient-starved BCG ∆bd at low molarity was comparable to the potency of bedaquiline, suggesting Q203 as a promising clinical candidate for the treatment of tuberculosis. We also observed that reduction in energy metabolism in dormant state may be a survival strategy undertaken by the bacilli to persist in nutrient-deprived conditions and our data further validated the importance of PMF and oxidative phosphorylation pathway as potential drug targets against dormant mycobacteria. Bachelor of Science in Biomedical Sciences 2016-08-10T08:03:36Z 2016-08-10T08:03:36Z 2016 Final Year Project (FYP) http://hdl.handle.net/10356/68930 en Nanyang Technological University 31 p. application/pdf
institution Nanyang Technological University
building NTU Library
continent Asia
country Singapore
Singapore
content_provider NTU Library
collection DR-NTU
language English
topic DRNTU::Science
spellingShingle DRNTU::Science
Foo, Joan Yuan Zhen
Terminal oxidases as potential drug targets in mycobacteria
description The main problem about tuberculosis treatment is the persistence of Mycobacterium tuberculosis despite prolonged chemotherapy. Hence, there is an urgent need to discover new drug targets to combat the dormant MDR/XDR bacilli. Nutrient-starvation triggers growth termination and renders them phenotypically drug-resistant. We conducted a series of experiments to study the feasibility of terminal oxidases i.e. cytochrome bd oxidase and cytochrome bc1-aa3 complex as potential drug targets in nutrient-starved mycobacteria by investigating the differences in energy metabolism, cell viability and drug susceptibility in nutrient-starved BCG ∆bd as compared to BCG WT and BCG ∆bd-pMV306-bd when treated with Q203, bedaquiline and INH. We concluded that combination of specific inhibitor of cytochrome bd oxidase with Q203 could have multiplicative effect against log-phase growing and dormant mycobacteria. Furthermore, potency of Q203 on nutrient-starved BCG ∆bd at low molarity was comparable to the potency of bedaquiline, suggesting Q203 as a promising clinical candidate for the treatment of tuberculosis. We also observed that reduction in energy metabolism in dormant state may be a survival strategy undertaken by the bacilli to persist in nutrient-deprived conditions and our data further validated the importance of PMF and oxidative phosphorylation pathway as potential drug targets against dormant mycobacteria.
author2 Kevin Pethe
author_facet Kevin Pethe
Foo, Joan Yuan Zhen
format Final Year Project
author Foo, Joan Yuan Zhen
author_sort Foo, Joan Yuan Zhen
title Terminal oxidases as potential drug targets in mycobacteria
title_short Terminal oxidases as potential drug targets in mycobacteria
title_full Terminal oxidases as potential drug targets in mycobacteria
title_fullStr Terminal oxidases as potential drug targets in mycobacteria
title_full_unstemmed Terminal oxidases as potential drug targets in mycobacteria
title_sort terminal oxidases as potential drug targets in mycobacteria
publishDate 2016
url http://hdl.handle.net/10356/68930
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