Drug discovery to reverse clarithromycin resistance in multidrug-resistant mycobacterium abscessus

Mycobacterium abscessus is an emerging life-threatening non-tuberculous mycobacterium with extensive drug-resistance mechanisms. M. abscessus infections have been causing substantial economic burden, due to the lengthy treatment lasting up to 24 months with multi-drug regimens. Despite this extensiv...

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Main Author: Dam, Linh Chi
Other Authors: Julien Lescar
Format: Final Year Project
Language:English
Published: 2019
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Online Access:http://hdl.handle.net/10356/78040
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Institution: Nanyang Technological University
Language: English
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spelling sg-ntu-dr.10356-780402023-02-28T17:59:51Z Drug discovery to reverse clarithromycin resistance in multidrug-resistant mycobacterium abscessus Dam, Linh Chi Julien Lescar Goh Boon Chong School of Biological Sciences Singapore-MIT Alliance Programme DRNTU::Science::Biological sciences Mycobacterium abscessus is an emerging life-threatening non-tuberculous mycobacterium with extensive drug-resistance mechanisms. M. abscessus infections have been causing substantial economic burden, due to the lengthy treatment lasting up to 24 months with multi-drug regimens. Despite this extensive treatment, M. abscessus infections still remain incurable. Thus, instead of developing new antibiotics, our objective is to identify an adjuvant that can be employed together with clarithromycin, its first-line treatment, to reverse clarithromycin resistance in M. abscessus. Clarithromycin resistance in M. abscessus is conferred by inducible erythromycin ribosome methylase (Erm) 41 enzyme. We first developed an optimized and novel induction protocol to induce clarithromycin resistance in M. abscessus, suitable for low cost and high-throughput drug screening. Two-stage screening was then used to screen nearly 2,200 compounds against resistant M. abscessus at single concentration (20 μM). Hits were validated as potential clarithromycin adjuvant in dose-response and checkerboard assay. Three promising adjuvant candidates were identified with good clarithromycin potentiation activity, with two have been validated to exert synergistic effect with clarithromycin while demonstrating negligible inhibition when used alone. Our approach of antibiotic adjuvant employing novel clarithromycin induction drug screening assay pave promising path to M. abscessus drug discovery and development. Bachelor of Science in Biological Sciences 2019-06-11T05:52:04Z 2019-06-11T05:52:04Z 2019 Final Year Project (FYP) http://hdl.handle.net/10356/78040 en Nanyang Technological University 35 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::Biological sciences
spellingShingle DRNTU::Science::Biological sciences
Dam, Linh Chi
Drug discovery to reverse clarithromycin resistance in multidrug-resistant mycobacterium abscessus
description Mycobacterium abscessus is an emerging life-threatening non-tuberculous mycobacterium with extensive drug-resistance mechanisms. M. abscessus infections have been causing substantial economic burden, due to the lengthy treatment lasting up to 24 months with multi-drug regimens. Despite this extensive treatment, M. abscessus infections still remain incurable. Thus, instead of developing new antibiotics, our objective is to identify an adjuvant that can be employed together with clarithromycin, its first-line treatment, to reverse clarithromycin resistance in M. abscessus. Clarithromycin resistance in M. abscessus is conferred by inducible erythromycin ribosome methylase (Erm) 41 enzyme. We first developed an optimized and novel induction protocol to induce clarithromycin resistance in M. abscessus, suitable for low cost and high-throughput drug screening. Two-stage screening was then used to screen nearly 2,200 compounds against resistant M. abscessus at single concentration (20 μM). Hits were validated as potential clarithromycin adjuvant in dose-response and checkerboard assay. Three promising adjuvant candidates were identified with good clarithromycin potentiation activity, with two have been validated to exert synergistic effect with clarithromycin while demonstrating negligible inhibition when used alone. Our approach of antibiotic adjuvant employing novel clarithromycin induction drug screening assay pave promising path to M. abscessus drug discovery and development.
author2 Julien Lescar
author_facet Julien Lescar
Dam, Linh Chi
format Final Year Project
author Dam, Linh Chi
author_sort Dam, Linh Chi
title Drug discovery to reverse clarithromycin resistance in multidrug-resistant mycobacterium abscessus
title_short Drug discovery to reverse clarithromycin resistance in multidrug-resistant mycobacterium abscessus
title_full Drug discovery to reverse clarithromycin resistance in multidrug-resistant mycobacterium abscessus
title_fullStr Drug discovery to reverse clarithromycin resistance in multidrug-resistant mycobacterium abscessus
title_full_unstemmed Drug discovery to reverse clarithromycin resistance in multidrug-resistant mycobacterium abscessus
title_sort drug discovery to reverse clarithromycin resistance in multidrug-resistant mycobacterium abscessus
publishDate 2019
url http://hdl.handle.net/10356/78040
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