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Extreme Drug Tolerance of Mycobacterium abscessus “Persisters”
Persistence of infection despite extensive chemotherapy with antibiotics displaying low MICs is a hallmark of lung disease caused by Mycobacterium abscessus (Mab). Thus, the classical MIC assay is a poor predictor of clinical outcome. Discovery of more efficacious antibiotics requires more predictiv...
Autores principales: | , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Frontiers Media S.A.
2020
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7064438/ https://www.ncbi.nlm.nih.gov/pubmed/32194537 http://dx.doi.org/10.3389/fmicb.2020.00359 |
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author | Yam, Yee-Kuen Alvarez, Nadine Go, Mei-Lin Dick, Thomas |
author_facet | Yam, Yee-Kuen Alvarez, Nadine Go, Mei-Lin Dick, Thomas |
author_sort | Yam, Yee-Kuen |
collection | PubMed |
description | Persistence of infection despite extensive chemotherapy with antibiotics displaying low MICs is a hallmark of lung disease caused by Mycobacterium abscessus (Mab). Thus, the classical MIC assay is a poor predictor of clinical outcome. Discovery of more efficacious antibiotics requires more predictive in vitro potency assays. As a mycobacterium, Mab is an obligate aerobe and a chemo-organo-heterotroph – it requires oxygen and organic carbon sources for growth. However, bacteria growing in patients can encounter micro-environmental conditions that are different from aerated nutrient-rich broth used to grow planktonic cultures for MIC assays. These in vivo conditions may include oxygen and nutrient limitation which should arrest growth. Furthermore, Mab was shown to grow as biofilms in vivo. Here, we show Mab Bamboo, a clinical isolate we use for Mab drug discovery, can survive oxygen deprivation and nutrient starvation for extended periods of time in non-replicating states and developed an in vitro model where the bacterium grows as biofilm. Using these culture models, we show that non-replicating or biofilm-growing bacteria display tolerance to clinically used anti-Mab antibiotics, consistent with the observed persistence of infection in patients. To demonstrate the utility of the developed “persister” assays for drug discovery, we determined the effect of novel agents targeting membrane functions against these physiological forms of the bacterium and find that these compounds show “anti-persister” activity. In conclusion, we developed in vitro “persister” assays to fill an assay gap in Mab drug discovery compound progression and to enable identification of novel lead compounds showing “anti-persister” activity. |
format | Online Article Text |
id | pubmed-7064438 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2020 |
publisher | Frontiers Media S.A. |
record_format | MEDLINE/PubMed |
spelling | pubmed-70644382020-03-19 Extreme Drug Tolerance of Mycobacterium abscessus “Persisters” Yam, Yee-Kuen Alvarez, Nadine Go, Mei-Lin Dick, Thomas Front Microbiol Microbiology Persistence of infection despite extensive chemotherapy with antibiotics displaying low MICs is a hallmark of lung disease caused by Mycobacterium abscessus (Mab). Thus, the classical MIC assay is a poor predictor of clinical outcome. Discovery of more efficacious antibiotics requires more predictive in vitro potency assays. As a mycobacterium, Mab is an obligate aerobe and a chemo-organo-heterotroph – it requires oxygen and organic carbon sources for growth. However, bacteria growing in patients can encounter micro-environmental conditions that are different from aerated nutrient-rich broth used to grow planktonic cultures for MIC assays. These in vivo conditions may include oxygen and nutrient limitation which should arrest growth. Furthermore, Mab was shown to grow as biofilms in vivo. Here, we show Mab Bamboo, a clinical isolate we use for Mab drug discovery, can survive oxygen deprivation and nutrient starvation for extended periods of time in non-replicating states and developed an in vitro model where the bacterium grows as biofilm. Using these culture models, we show that non-replicating or biofilm-growing bacteria display tolerance to clinically used anti-Mab antibiotics, consistent with the observed persistence of infection in patients. To demonstrate the utility of the developed “persister” assays for drug discovery, we determined the effect of novel agents targeting membrane functions against these physiological forms of the bacterium and find that these compounds show “anti-persister” activity. In conclusion, we developed in vitro “persister” assays to fill an assay gap in Mab drug discovery compound progression and to enable identification of novel lead compounds showing “anti-persister” activity. Frontiers Media S.A. 2020-03-04 /pmc/articles/PMC7064438/ /pubmed/32194537 http://dx.doi.org/10.3389/fmicb.2020.00359 Text en Copyright © 2020 Yam, Alvarez, Go and Dick. 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 Yam, Yee-Kuen Alvarez, Nadine Go, Mei-Lin Dick, Thomas Extreme Drug Tolerance of Mycobacterium abscessus “Persisters” |
title | Extreme Drug Tolerance of Mycobacterium abscessus “Persisters” |
title_full | Extreme Drug Tolerance of Mycobacterium abscessus “Persisters” |
title_fullStr | Extreme Drug Tolerance of Mycobacterium abscessus “Persisters” |
title_full_unstemmed | Extreme Drug Tolerance of Mycobacterium abscessus “Persisters” |
title_short | Extreme Drug Tolerance of Mycobacterium abscessus “Persisters” |
title_sort | extreme drug tolerance of mycobacterium abscessus “persisters” |
topic | Microbiology |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7064438/ https://www.ncbi.nlm.nih.gov/pubmed/32194537 http://dx.doi.org/10.3389/fmicb.2020.00359 |
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