Novel Antimicrobials from Uncultured Bacteria Acting against <named-content content-type="genus-species">Mycobacterium tuberculosis</named-content>

ABSTRACT Mycobacterium tuberculosis, which causes tuberculosis (TB), is estimated to infect one-third of the world’s population. The overall burden and the emergence of drug-resistant strains of Mycobacterium tuberculosis underscore the need for new therapeutic options against this important human p...

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Autores principales:	Jeffrey Quigley, Aaron Peoples, Asel Sarybaeva, Dallas Hughes, Meghan Ghiglieri, Catherine Achorn, Alysha Desrosiers, Cintia Felix, Libang Liang, Stephanie Malveira, William Millett, Anthony Nitti, Baldwin Tran, Ashley Zullo, Clemens Anklin, Amy Spoering, Losee Lucy Ling, Kim Lewis
Formato:	article
Lenguaje:	EN
Publicado:	American Society for Microbiology 2020
Materias:	drug discovery Mycobacterium tuberculosis natural product discovery nontuberculous mycobacteria Sec translocation antibiotic Microbiology QR1-502
Acceso en línea:	https://doaj.org/article/305acec522f24422abf81c8aedef776e
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spelling	oai:doaj.org-article:305acec522f24422abf81c8aedef776e2021-11-15T15:56:44ZNovel Antimicrobials from Uncultured Bacteria Acting against <named-content content-type="genus-species">Mycobacterium tuberculosis</named-content>10.1128/mBio.01516-202150-7511https://doaj.org/article/305acec522f24422abf81c8aedef776e2020-08-01T00:00:00Zhttps://journals.asm.org/doi/10.1128/mBio.01516-20https://doaj.org/toc/2150-7511ABSTRACT Mycobacterium tuberculosis, which causes tuberculosis (TB), is estimated to infect one-third of the world’s population. The overall burden and the emergence of drug-resistant strains of Mycobacterium tuberculosis underscore the need for new therapeutic options against this important human pathogen. Our recent work demonstrated the success of natural product discovery in identifying novel compounds with efficacy against Mycobacterium tuberculosis. Here, we improve on these methods by combining improved isolation and Mycobacterium tuberculosis selective screening to identify three new anti-TB compounds: streptomycobactin, kitamycobactin, and amycobactin. We were unable to obtain mutants resistant to streptomycobactin, and its target remains to be elucidated. We identify the target of kitamycobactin to be the mycobacterial ClpP1P2C1 protease and confirm that kitamycobactin is an analog of the previously identified compound lassomycin. Further, we identify the target of amycobactin to be the essential protein secretion pore SecY. We show further that amycobactin inhibits protein secretion via the SecY translocon. Importantly, this inhibition is bactericidal to nonreplicating Mycobacterium tuberculosis. This is the first compound, to our knowledge, that targets the Sec protein secretion machinery in Mycobacterium tuberculosis. This work underscores the ability of natural product discovery to deliver not only new compounds with activity against Mycobacterium tuberculosis but also compounds with novel targets. IMPORTANCE Decreasing discovery rates and increasing resistance have underscored the need for novel therapeutic options to treat Mycobacterium tuberculosis infection. Here, we screen extracts from previously uncultured soil microbes for specific activity against Mycobacterium tuberculosis, identifying three novel compounds. We further define the mechanism of action of one compound, amycobactin, and demonstrate that it inhibits protein secretion through the Sec translocation machinery.Jeffrey QuigleyAaron PeoplesAsel SarybaevaDallas HughesMeghan GhiglieriCatherine AchornAlysha DesrosiersCintia FelixLibang LiangStephanie MalveiraWilliam MillettAnthony NittiBaldwin TranAshley ZulloClemens AnklinAmy SpoeringLosee Lucy LingKim LewisAmerican Society for Microbiologyarticledrug discoveryMycobacterium tuberculosisnatural product discoverynontuberculous mycobacteriaSec translocationantibioticMicrobiologyQR1-502ENmBio, Vol 11, Iss 4 (2020)
institution	DOAJ
collection	DOAJ
language	EN
topic	drug discovery Mycobacterium tuberculosis natural product discovery nontuberculous mycobacteria Sec translocation antibiotic Microbiology QR1-502
spellingShingle	drug discovery Mycobacterium tuberculosis natural product discovery nontuberculous mycobacteria Sec translocation antibiotic Microbiology QR1-502 Jeffrey Quigley Aaron Peoples Asel Sarybaeva Dallas Hughes Meghan Ghiglieri Catherine Achorn Alysha Desrosiers Cintia Felix Libang Liang Stephanie Malveira William Millett Anthony Nitti Baldwin Tran Ashley Zullo Clemens Anklin Amy Spoering Losee Lucy Ling Kim Lewis Novel Antimicrobials from Uncultured Bacteria Acting against <named-content content-type="genus-species">Mycobacterium tuberculosis</named-content>
description	ABSTRACT Mycobacterium tuberculosis, which causes tuberculosis (TB), is estimated to infect one-third of the world’s population. The overall burden and the emergence of drug-resistant strains of Mycobacterium tuberculosis underscore the need for new therapeutic options against this important human pathogen. Our recent work demonstrated the success of natural product discovery in identifying novel compounds with efficacy against Mycobacterium tuberculosis. Here, we improve on these methods by combining improved isolation and Mycobacterium tuberculosis selective screening to identify three new anti-TB compounds: streptomycobactin, kitamycobactin, and amycobactin. We were unable to obtain mutants resistant to streptomycobactin, and its target remains to be elucidated. We identify the target of kitamycobactin to be the mycobacterial ClpP1P2C1 protease and confirm that kitamycobactin is an analog of the previously identified compound lassomycin. Further, we identify the target of amycobactin to be the essential protein secretion pore SecY. We show further that amycobactin inhibits protein secretion via the SecY translocon. Importantly, this inhibition is bactericidal to nonreplicating Mycobacterium tuberculosis. This is the first compound, to our knowledge, that targets the Sec protein secretion machinery in Mycobacterium tuberculosis. This work underscores the ability of natural product discovery to deliver not only new compounds with activity against Mycobacterium tuberculosis but also compounds with novel targets. IMPORTANCE Decreasing discovery rates and increasing resistance have underscored the need for novel therapeutic options to treat Mycobacterium tuberculosis infection. Here, we screen extracts from previously uncultured soil microbes for specific activity against Mycobacterium tuberculosis, identifying three novel compounds. We further define the mechanism of action of one compound, amycobactin, and demonstrate that it inhibits protein secretion through the Sec translocation machinery.
format	article
author	Jeffrey Quigley Aaron Peoples Asel Sarybaeva Dallas Hughes Meghan Ghiglieri Catherine Achorn Alysha Desrosiers Cintia Felix Libang Liang Stephanie Malveira William Millett Anthony Nitti Baldwin Tran Ashley Zullo Clemens Anklin Amy Spoering Losee Lucy Ling Kim Lewis
author_facet	Jeffrey Quigley Aaron Peoples Asel Sarybaeva Dallas Hughes Meghan Ghiglieri Catherine Achorn Alysha Desrosiers Cintia Felix Libang Liang Stephanie Malveira William Millett Anthony Nitti Baldwin Tran Ashley Zullo Clemens Anklin Amy Spoering Losee Lucy Ling Kim Lewis
author_sort	Jeffrey Quigley
title	Novel Antimicrobials from Uncultured Bacteria Acting against <named-content content-type="genus-species">Mycobacterium tuberculosis</named-content>
title_short	Novel Antimicrobials from Uncultured Bacteria Acting against <named-content content-type="genus-species">Mycobacterium tuberculosis</named-content>
title_full	Novel Antimicrobials from Uncultured Bacteria Acting against <named-content content-type="genus-species">Mycobacterium tuberculosis</named-content>
title_fullStr	Novel Antimicrobials from Uncultured Bacteria Acting against <named-content content-type="genus-species">Mycobacterium tuberculosis</named-content>
title_full_unstemmed	Novel Antimicrobials from Uncultured Bacteria Acting against <named-content content-type="genus-species">Mycobacterium tuberculosis</named-content>
title_sort	novel antimicrobials from uncultured bacteria acting against <named-content content-type="genus-species">mycobacterium tuberculosis</named-content>
publisher	American Society for Microbiology
publishDate	2020
url	https://doaj.org/article/305acec522f24422abf81c8aedef776e
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Novel Antimicrobials from Uncultured Bacteria Acting against <named-content content-type="genus-species">Mycobacterium tuberculosis</named-content>

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