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The Mycobacterial Membrane: A Novel Target Space for Anti-tubercular Drugs
Tuberculosis (TB) poses an enduring threat to global health. Consistently ranked among the top 10 causes of death worldwide since 2000, TB has now exceeded HIV-AIDS in terms of deaths inflicted by a single infectious agent. In spite of recently declining TB incident rates, these decreases have been...
Autores principales: | , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
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Frontiers Media S.A.
2018
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6060259/ https://www.ncbi.nlm.nih.gov/pubmed/30072978 http://dx.doi.org/10.3389/fmicb.2018.01627 |
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author | Chen, Huan Nyantakyi, Samuel A. Li, Ming Gopal, Pooja Aziz, Dinah B. Yang, Tianming Moreira, Wilfried Gengenbacher, Martin Dick, Thomas Go, Mei L. |
author_facet | Chen, Huan Nyantakyi, Samuel A. Li, Ming Gopal, Pooja Aziz, Dinah B. Yang, Tianming Moreira, Wilfried Gengenbacher, Martin Dick, Thomas Go, Mei L. |
author_sort | Chen, Huan |
collection | PubMed |
description | Tuberculosis (TB) poses an enduring threat to global health. Consistently ranked among the top 10 causes of death worldwide since 2000, TB has now exceeded HIV-AIDS in terms of deaths inflicted by a single infectious agent. In spite of recently declining TB incident rates, these decreases have been incremental and fall short of threshold levels required to end the global TB epidemic. As in other infectious diseases, the emergence of resistant organisms poses a major impediment to effective TB control. Resistance in mycobacteria may evolve from genetic mutations in target genes which are transmitted during cell multiplication from mother cells to their progeny. A more insidious form of resistance involves sub-populations of non-growing (“dormant”) mycobacterial persisters. Quiescent and genetically identical to their susceptible counterparts, persisters exhibit non-inheritable drug tolerance. Their prevalence account for the protracted treatment period that is required for the treatment of TB. In order to improve the efficacy of treatment against mycobacterial persisters and drug-resistant organisms, novel antitubercular agents are urgently required. Selective targeting of bacterial membranes has been proposed as a viable therapeutic strategy against infectious diseases. The underpinning rationale is that a functionally intact cell membrane is vital for both replicating and dormant bacteria. Perturbing the membrane would thus disrupt a multitude of embedded targets with lethal pleiotropic consequences, besides limiting the emergence of resistant strains. There is growing interest in exploring small molecules as selective disruptors of the mycobacterial membrane. In this review, we examined the recent literature on different chemotypes with membrane perturbing properties, the mechanisms by which they induce membrane disruption and their potential as anti-TB agents. Cationic amphiphilicity is a signature motif that is required of membrane targeting agents but adherence to this broad physical requirement does not necessarily translate to conformity in terms of biological outcomes. Nor does it ensure selective targeting of mycobacterial membranes. These are unresolved issues that require further investigation. |
format | Online Article Text |
id | pubmed-6060259 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2018 |
publisher | Frontiers Media S.A. |
record_format | MEDLINE/PubMed |
spelling | pubmed-60602592018-08-02 The Mycobacterial Membrane: A Novel Target Space for Anti-tubercular Drugs Chen, Huan Nyantakyi, Samuel A. Li, Ming Gopal, Pooja Aziz, Dinah B. Yang, Tianming Moreira, Wilfried Gengenbacher, Martin Dick, Thomas Go, Mei L. Front Microbiol Microbiology Tuberculosis (TB) poses an enduring threat to global health. Consistently ranked among the top 10 causes of death worldwide since 2000, TB has now exceeded HIV-AIDS in terms of deaths inflicted by a single infectious agent. In spite of recently declining TB incident rates, these decreases have been incremental and fall short of threshold levels required to end the global TB epidemic. As in other infectious diseases, the emergence of resistant organisms poses a major impediment to effective TB control. Resistance in mycobacteria may evolve from genetic mutations in target genes which are transmitted during cell multiplication from mother cells to their progeny. A more insidious form of resistance involves sub-populations of non-growing (“dormant”) mycobacterial persisters. Quiescent and genetically identical to their susceptible counterparts, persisters exhibit non-inheritable drug tolerance. Their prevalence account for the protracted treatment period that is required for the treatment of TB. In order to improve the efficacy of treatment against mycobacterial persisters and drug-resistant organisms, novel antitubercular agents are urgently required. Selective targeting of bacterial membranes has been proposed as a viable therapeutic strategy against infectious diseases. The underpinning rationale is that a functionally intact cell membrane is vital for both replicating and dormant bacteria. Perturbing the membrane would thus disrupt a multitude of embedded targets with lethal pleiotropic consequences, besides limiting the emergence of resistant strains. There is growing interest in exploring small molecules as selective disruptors of the mycobacterial membrane. In this review, we examined the recent literature on different chemotypes with membrane perturbing properties, the mechanisms by which they induce membrane disruption and their potential as anti-TB agents. Cationic amphiphilicity is a signature motif that is required of membrane targeting agents but adherence to this broad physical requirement does not necessarily translate to conformity in terms of biological outcomes. Nor does it ensure selective targeting of mycobacterial membranes. These are unresolved issues that require further investigation. Frontiers Media S.A. 2018-07-19 /pmc/articles/PMC6060259/ /pubmed/30072978 http://dx.doi.org/10.3389/fmicb.2018.01627 Text en Copyright © 2018 Chen, Nyantakyi, Li, Gopal, Aziz, Yang, Moreira, Gengenbacher, Dick and Go. http://creativecommons.org/licenses/by/4.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms. |
spellingShingle | Microbiology Chen, Huan Nyantakyi, Samuel A. Li, Ming Gopal, Pooja Aziz, Dinah B. Yang, Tianming Moreira, Wilfried Gengenbacher, Martin Dick, Thomas Go, Mei L. The Mycobacterial Membrane: A Novel Target Space for Anti-tubercular Drugs |
title | The Mycobacterial Membrane: A Novel Target Space for Anti-tubercular Drugs |
title_full | The Mycobacterial Membrane: A Novel Target Space for Anti-tubercular Drugs |
title_fullStr | The Mycobacterial Membrane: A Novel Target Space for Anti-tubercular Drugs |
title_full_unstemmed | The Mycobacterial Membrane: A Novel Target Space for Anti-tubercular Drugs |
title_short | The Mycobacterial Membrane: A Novel Target Space for Anti-tubercular Drugs |
title_sort | mycobacterial membrane: a novel target space for anti-tubercular drugs |
topic | Microbiology |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6060259/ https://www.ncbi.nlm.nih.gov/pubmed/30072978 http://dx.doi.org/10.3389/fmicb.2018.01627 |
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