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Article: Digging deeper to save the old anti-tuberculosis target: D-alanine-D-alanine ligase with a novel inhibitor, IMB-0283

TitleDigging deeper to save the old anti-tuberculosis target: D-alanine-D-alanine ligase with a novel inhibitor, IMB-0283
Authors
KeywordsMycobacterium tuberculosis
drug-resistance
D-alanine–D-alanine ligase
inhibitor
D-cycloserine
Issue Date2020
PublisherFrontiers Research Foundation. The Journal's web site is located at http://www.frontiersin.org/microbiology/
Citation
Frontiers in Microbiology, 2020, v. 10, p. article no. 3017 How to Cite?
AbstractThe emergence of drug-resistant Mycobacterium tuberculosis (Mtb) has hampered treatments for tuberculosis, which consequently now require novel agents to overcome such drug resistance. The genetically stable D-alanine–D-alanine ligase A (DdlA) has been deemed as an excellent therapeutic target for tuberculosis. In the present study, a competitive inhibitor (IMB-0283) of DdlA was obtained via high-throughput screening. The minimum inhibitory concentrations (MIC) of IMB-0283 for the standard and clinical drug-resistant Mtb strains ranged from 0.25 to 4.00 μg/mL, whereas the conventional inhibitor of DdlA, D-cycloserine (DCS), only inhibited the growth of the standard Mtb strain at 16 μg/mL. The lethal effect of IMB-0283 on Mtb was found to act intracellularly in a DdlA-dependent manner. Specifically, IMB-0283 prevented the synthesis of neonatal cell walls but did not damage mature cell walls. Compared with those of DCS, IMB-0283 exhibited lower cytotoxicity and a higher selective index (SI). At the same dosages of treatment, IMB-0283 reduced bacterial load (log CFU/mL) in an acute animal model from 5.58 to 4.40, while DCS did not yield any such treatment efficacy. Taken together, the lower cytotoxicity and more efficacious in vivo activity of IMB-0283 suggest that it is a promising lead compound for antituberculosis drug development.
Persistent Identifierhttp://hdl.handle.net/10722/286685
ISSN
2019 Impact Factor: 4.235
2015 SCImago Journal Rankings: 1.970
PubMed Central ID

 

DC FieldValueLanguage
dc.contributor.authorMeng, J.-
dc.contributor.authorGao, P-
dc.contributor.authorWang, X-
dc.contributor.authorGuan, Y-
dc.contributor.authorLiu, Y-
dc.contributor.authorXiao, C-
dc.date.accessioned2020-09-04T13:28:59Z-
dc.date.available2020-09-04T13:28:59Z-
dc.date.issued2020-
dc.identifier.citationFrontiers in Microbiology, 2020, v. 10, p. article no. 3017-
dc.identifier.issn1664-302X-
dc.identifier.urihttp://hdl.handle.net/10722/286685-
dc.description.abstractThe emergence of drug-resistant Mycobacterium tuberculosis (Mtb) has hampered treatments for tuberculosis, which consequently now require novel agents to overcome such drug resistance. The genetically stable D-alanine–D-alanine ligase A (DdlA) has been deemed as an excellent therapeutic target for tuberculosis. In the present study, a competitive inhibitor (IMB-0283) of DdlA was obtained via high-throughput screening. The minimum inhibitory concentrations (MIC) of IMB-0283 for the standard and clinical drug-resistant Mtb strains ranged from 0.25 to 4.00 μg/mL, whereas the conventional inhibitor of DdlA, D-cycloserine (DCS), only inhibited the growth of the standard Mtb strain at 16 μg/mL. The lethal effect of IMB-0283 on Mtb was found to act intracellularly in a DdlA-dependent manner. Specifically, IMB-0283 prevented the synthesis of neonatal cell walls but did not damage mature cell walls. Compared with those of DCS, IMB-0283 exhibited lower cytotoxicity and a higher selective index (SI). At the same dosages of treatment, IMB-0283 reduced bacterial load (log CFU/mL) in an acute animal model from 5.58 to 4.40, while DCS did not yield any such treatment efficacy. Taken together, the lower cytotoxicity and more efficacious in vivo activity of IMB-0283 suggest that it is a promising lead compound for antituberculosis drug development.-
dc.languageeng-
dc.publisherFrontiers Research Foundation. The Journal's web site is located at http://www.frontiersin.org/microbiology/-
dc.relation.ispartofFrontiers in Microbiology-
dc.rightsThis Document is Protected by copyright and was first published by Frontiers. All rights reserved. It is reproduced with permission.-
dc.rightsThis work is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License.-
dc.subjectMycobacterium tuberculosis-
dc.subjectdrug-resistance-
dc.subjectD-alanine–D-alanine ligase-
dc.subjectinhibitor-
dc.subjectD-cycloserine-
dc.titleDigging deeper to save the old anti-tuberculosis target: D-alanine-D-alanine ligase with a novel inhibitor, IMB-0283-
dc.typeArticle-
dc.identifier.emailGao, P: gaopeng@hku.hk-
dc.description.naturepublished_or_final_version-
dc.identifier.doi10.3389/fmicb.2019.03017-
dc.identifier.pmid32010089-
dc.identifier.pmcidPMC6974524-
dc.identifier.scopuseid_2-s2.0-85078802292-
dc.identifier.hkuros314023-
dc.identifier.volume10-
dc.identifier.spagearticle no. 3017-
dc.identifier.epagearticle no. 3017-
dc.publisher.placeSwitzerland-

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