Rapid, serial, non-invasive assessment of drug efficacy in mice with autoluminescent Mycobacterium ulcerans infection.
Buruli ulcer (BU) caused by Mycobacterium ulcerans is the world's third most common mycobacterial infection. There is no vaccine against BU and surgery is needed for patients with large ulcers. Although recent experience indicates combination chemotherapy with streptomycin and rifampin improves...
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ftdoajarticles:oai:doaj.org/article:2febf03bf173482dab64c29be2f416e5 2023-05-15T15:15:20+02:00 Rapid, serial, non-invasive assessment of drug efficacy in mice with autoluminescent Mycobacterium ulcerans infection. Tianyu Zhang Si-Yang Li Paul J Converse Jacques H Grosset Eric L Nuermberger 2013-01-01T00:00:00Z https://doi.org/10.1371/journal.pntd.0002598 https://doaj.org/article/2febf03bf173482dab64c29be2f416e5 EN eng Public Library of Science (PLoS) http://europepmc.org/articles/PMC3868507?pdf=render https://doaj.org/toc/1935-2727 https://doaj.org/toc/1935-2735 1935-2727 1935-2735 doi:10.1371/journal.pntd.0002598 https://doaj.org/article/2febf03bf173482dab64c29be2f416e5 PLoS Neglected Tropical Diseases, Vol 7, Iss 12, p e2598 (2013) Arctic medicine. Tropical medicine RC955-962 Public aspects of medicine RA1-1270 article 2013 ftdoajarticles https://doi.org/10.1371/journal.pntd.0002598 2022-12-31T06:04:08Z Buruli ulcer (BU) caused by Mycobacterium ulcerans is the world's third most common mycobacterial infection. There is no vaccine against BU and surgery is needed for patients with large ulcers. Although recent experience indicates combination chemotherapy with streptomycin and rifampin improves cure rates, the utility of this regimen is limited by the 2-month duration of therapy, potential toxicity and required parenteral administration of streptomycin, and drug-drug interactions caused by rifampin. Discovery and development of drugs for BU is greatly hampered by the slow growth rate of M. ulcerans, requiring up to 3 months of incubation on solid media to produce colonies. Surrogate markers for evaluating antimicrobial activity in real-time which can be measured serially and non-invasively in infected footpads of live mice would accelerate pre-clinical evaluation of new drugs to treat BU. Previously, we developed bioluminescent M. ulcerans strains, demonstrating proof of concept for measuring luminescence as a surrogate marker for viable M. ulcerans in vitro and in vivo. However, the requirement of exogenous substrate limited the utility of such strains, especially for in vivo experiments.For this study, we engineered M. ulcerans strains that express the entire luxCDABE operon and therefore are autoluminescent due to endogenous substrate production. The selected reporter strain displayed a growth rate and virulence similar to the wild-type parent strain and enabled rapid, real-time monitoring of in vitro and in vivo drug activity, including serial, non-invasive assessments in live mice, producing results which correlated closely with colony-forming unit (CFU) counts for a panel of drugs with various mechanisms of action.Our results indicate that autoluminescent reporter strains of M. ulcerans are exceptional tools for pre-clinical evaluation of new drugs to treat BU due to their potential to drastically reduce the time, effort, animals, compound, and costs required to evaluate drug activity. Article in Journal/Newspaper Arctic Directory of Open Access Journals: DOAJ Articles Arctic PLoS Neglected Tropical Diseases 7 12 e2598 |
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Directory of Open Access Journals: DOAJ Articles |
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English |
topic |
Arctic medicine. Tropical medicine RC955-962 Public aspects of medicine RA1-1270 |
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Arctic medicine. Tropical medicine RC955-962 Public aspects of medicine RA1-1270 Tianyu Zhang Si-Yang Li Paul J Converse Jacques H Grosset Eric L Nuermberger Rapid, serial, non-invasive assessment of drug efficacy in mice with autoluminescent Mycobacterium ulcerans infection. |
topic_facet |
Arctic medicine. Tropical medicine RC955-962 Public aspects of medicine RA1-1270 |
description |
Buruli ulcer (BU) caused by Mycobacterium ulcerans is the world's third most common mycobacterial infection. There is no vaccine against BU and surgery is needed for patients with large ulcers. Although recent experience indicates combination chemotherapy with streptomycin and rifampin improves cure rates, the utility of this regimen is limited by the 2-month duration of therapy, potential toxicity and required parenteral administration of streptomycin, and drug-drug interactions caused by rifampin. Discovery and development of drugs for BU is greatly hampered by the slow growth rate of M. ulcerans, requiring up to 3 months of incubation on solid media to produce colonies. Surrogate markers for evaluating antimicrobial activity in real-time which can be measured serially and non-invasively in infected footpads of live mice would accelerate pre-clinical evaluation of new drugs to treat BU. Previously, we developed bioluminescent M. ulcerans strains, demonstrating proof of concept for measuring luminescence as a surrogate marker for viable M. ulcerans in vitro and in vivo. However, the requirement of exogenous substrate limited the utility of such strains, especially for in vivo experiments.For this study, we engineered M. ulcerans strains that express the entire luxCDABE operon and therefore are autoluminescent due to endogenous substrate production. The selected reporter strain displayed a growth rate and virulence similar to the wild-type parent strain and enabled rapid, real-time monitoring of in vitro and in vivo drug activity, including serial, non-invasive assessments in live mice, producing results which correlated closely with colony-forming unit (CFU) counts for a panel of drugs with various mechanisms of action.Our results indicate that autoluminescent reporter strains of M. ulcerans are exceptional tools for pre-clinical evaluation of new drugs to treat BU due to their potential to drastically reduce the time, effort, animals, compound, and costs required to evaluate drug activity. |
format |
Article in Journal/Newspaper |
author |
Tianyu Zhang Si-Yang Li Paul J Converse Jacques H Grosset Eric L Nuermberger |
author_facet |
Tianyu Zhang Si-Yang Li Paul J Converse Jacques H Grosset Eric L Nuermberger |
author_sort |
Tianyu Zhang |
title |
Rapid, serial, non-invasive assessment of drug efficacy in mice with autoluminescent Mycobacterium ulcerans infection. |
title_short |
Rapid, serial, non-invasive assessment of drug efficacy in mice with autoluminescent Mycobacterium ulcerans infection. |
title_full |
Rapid, serial, non-invasive assessment of drug efficacy in mice with autoluminescent Mycobacterium ulcerans infection. |
title_fullStr |
Rapid, serial, non-invasive assessment of drug efficacy in mice with autoluminescent Mycobacterium ulcerans infection. |
title_full_unstemmed |
Rapid, serial, non-invasive assessment of drug efficacy in mice with autoluminescent Mycobacterium ulcerans infection. |
title_sort |
rapid, serial, non-invasive assessment of drug efficacy in mice with autoluminescent mycobacterium ulcerans infection. |
publisher |
Public Library of Science (PLoS) |
publishDate |
2013 |
url |
https://doi.org/10.1371/journal.pntd.0002598 https://doaj.org/article/2febf03bf173482dab64c29be2f416e5 |
geographic |
Arctic |
geographic_facet |
Arctic |
genre |
Arctic |
genre_facet |
Arctic |
op_source |
PLoS Neglected Tropical Diseases, Vol 7, Iss 12, p e2598 (2013) |
op_relation |
http://europepmc.org/articles/PMC3868507?pdf=render https://doaj.org/toc/1935-2727 https://doaj.org/toc/1935-2735 1935-2727 1935-2735 doi:10.1371/journal.pntd.0002598 https://doaj.org/article/2febf03bf173482dab64c29be2f416e5 |
op_doi |
https://doi.org/10.1371/journal.pntd.0002598 |
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PLoS Neglected Tropical Diseases |
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7 |
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12 |
container_start_page |
e2598 |
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