Keto-Mycolic Acid-Dependent Pellicle Formation Confers Tolerance to Drug-Sensitive <named-content content-type="genus-species">Mycobacterium tuberculosis</named-content>

ABSTRACT The chronic nature of tuberculosis (TB), its requirement of long duration of treatment, its ability to evade immune intervention, and its propensity to relapse after drug treatment is discontinued are reminiscent of other chronic, biofilm-associated bacterial diseases. Historically, Mycobac...

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Autores principales:	Dhinakaran Sambandan, Dee N. Dao, Brian C. Weinrick, Catherine Vilchèze, Sudagar S. Gurcha, Anil Ojha, Laurent Kremer, Gurdyal S. Besra, Graham F. Hatfull, William R. Jacobs
Formato:	article
Lenguaje:	EN
Publicado:	American Society for Microbiology 2013
Materias:	Microbiology QR1-502
Acceso en línea:	https://doaj.org/article/0e4ca69911e645169334c63c251a3526
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spelling	oai:doaj.org-article:0e4ca69911e645169334c63c251a35262021-11-15T15:40:05ZKeto-Mycolic Acid-Dependent Pellicle Formation Confers Tolerance to Drug-Sensitive <named-content content-type="genus-species">Mycobacterium tuberculosis</named-content>10.1128/mBio.00222-132150-7511https://doaj.org/article/0e4ca69911e645169334c63c251a35262013-07-01T00:00:00Zhttps://journals.asm.org/doi/10.1128/mBio.00222-13https://doaj.org/toc/2150-7511ABSTRACT The chronic nature of tuberculosis (TB), its requirement of long duration of treatment, its ability to evade immune intervention, and its propensity to relapse after drug treatment is discontinued are reminiscent of other chronic, biofilm-associated bacterial diseases. Historically, Mycobacterium tuberculosis was grown as a pellicle, a biofilm-like structure, at the liquid-air interface in a variety of synthetic media. Notably, the most widely administered human vaccine, BCG, is grown as a pellicle for vaccine production. However, the molecular requirements for this growth remain ill defined. Here, we demonstrate that keto-mycolic acids (keto-MA) are essential for pellicle growth, and mutants lacking in or depleted of this MA species are unable to form a pellicle. We investigated the role of the pellicle biofilm in the reduction of antibiotic sensitivity known as drug tolerance using the pellicle-defective ΔmmaA4 mutant strain. We discovered that the ΔmmaA4 mutant, which is both pellicle defective and highly sensitive to rifampicin (RIF) under planktonic growth, when incorporated within the wild-type pellicle biofilm, was protected from the bactericidal activity of RIF. The observation that growth within the M. tuberculosis pellicle biofilm can confer drug tolerance to a drug-hypersensitive strain suggests that identifying molecular requirements for pellicle growth could lead to development of novel interventions against mycobacterial infections. Our findings also suggest that a class of drugs that can disrupt M. tuberculosis biofilm formation, when used in conjunction with conventional antibiotics, has the potential to overcome drug tolerance. IMPORTANCE Two of the most important questions in tuberculosis (TB) research are (i) how does Mycobacterium tuberculosis persist in the human host for decades in the face of an active immune response and (ii) why does it take six months and four drugs to treat uncomplicated TB. Both these aspects of M. tuberculosis biology are reminiscent of infections caused by organisms capable of forming biofilms. M. tuberculosis is capable of growing as a biofilm-like structure called the pellicle. In this study, we demonstrate that a specific cell wall component, keto-mycolic acid, is essential for pellicle growth. We also demonstrate that a strain of M. tuberculosis that is both drug sensitive and pellicle defective exhibits commensal behavior and becomes drug tolerant by becoming part of a heterogeneous pellicle, a characteristic of multispecies biofilms. These observations could have important implications for identifying novel pathways for M. tuberculosis drug tolerance and the design of new modalities to rapidly treat TB.Dhinakaran SambandanDee N. DaoBrian C. WeinrickCatherine VilchèzeSudagar S. GurchaAnil OjhaLaurent KremerGurdyal S. BesraGraham F. HatfullWilliam R. JacobsAmerican Society for MicrobiologyarticleMicrobiologyQR1-502ENmBio, Vol 4, Iss 3 (2013)
institution	DOAJ
collection	DOAJ
language	EN
topic	Microbiology QR1-502
spellingShingle	Microbiology QR1-502 Dhinakaran Sambandan Dee N. Dao Brian C. Weinrick Catherine Vilchèze Sudagar S. Gurcha Anil Ojha Laurent Kremer Gurdyal S. Besra Graham F. Hatfull William R. Jacobs Keto-Mycolic Acid-Dependent Pellicle Formation Confers Tolerance to Drug-Sensitive <named-content content-type="genus-species">Mycobacterium tuberculosis</named-content>
description	ABSTRACT The chronic nature of tuberculosis (TB), its requirement of long duration of treatment, its ability to evade immune intervention, and its propensity to relapse after drug treatment is discontinued are reminiscent of other chronic, biofilm-associated bacterial diseases. Historically, Mycobacterium tuberculosis was grown as a pellicle, a biofilm-like structure, at the liquid-air interface in a variety of synthetic media. Notably, the most widely administered human vaccine, BCG, is grown as a pellicle for vaccine production. However, the molecular requirements for this growth remain ill defined. Here, we demonstrate that keto-mycolic acids (keto-MA) are essential for pellicle growth, and mutants lacking in or depleted of this MA species are unable to form a pellicle. We investigated the role of the pellicle biofilm in the reduction of antibiotic sensitivity known as drug tolerance using the pellicle-defective ΔmmaA4 mutant strain. We discovered that the ΔmmaA4 mutant, which is both pellicle defective and highly sensitive to rifampicin (RIF) under planktonic growth, when incorporated within the wild-type pellicle biofilm, was protected from the bactericidal activity of RIF. The observation that growth within the M. tuberculosis pellicle biofilm can confer drug tolerance to a drug-hypersensitive strain suggests that identifying molecular requirements for pellicle growth could lead to development of novel interventions against mycobacterial infections. Our findings also suggest that a class of drugs that can disrupt M. tuberculosis biofilm formation, when used in conjunction with conventional antibiotics, has the potential to overcome drug tolerance. IMPORTANCE Two of the most important questions in tuberculosis (TB) research are (i) how does Mycobacterium tuberculosis persist in the human host for decades in the face of an active immune response and (ii) why does it take six months and four drugs to treat uncomplicated TB. Both these aspects of M. tuberculosis biology are reminiscent of infections caused by organisms capable of forming biofilms. M. tuberculosis is capable of growing as a biofilm-like structure called the pellicle. In this study, we demonstrate that a specific cell wall component, keto-mycolic acid, is essential for pellicle growth. We also demonstrate that a strain of M. tuberculosis that is both drug sensitive and pellicle defective exhibits commensal behavior and becomes drug tolerant by becoming part of a heterogeneous pellicle, a characteristic of multispecies biofilms. These observations could have important implications for identifying novel pathways for M. tuberculosis drug tolerance and the design of new modalities to rapidly treat TB.
format	article
author	Dhinakaran Sambandan Dee N. Dao Brian C. Weinrick Catherine Vilchèze Sudagar S. Gurcha Anil Ojha Laurent Kremer Gurdyal S. Besra Graham F. Hatfull William R. Jacobs
author_facet	Dhinakaran Sambandan Dee N. Dao Brian C. Weinrick Catherine Vilchèze Sudagar S. Gurcha Anil Ojha Laurent Kremer Gurdyal S. Besra Graham F. Hatfull William R. Jacobs
author_sort	Dhinakaran Sambandan
title	Keto-Mycolic Acid-Dependent Pellicle Formation Confers Tolerance to Drug-Sensitive <named-content content-type="genus-species">Mycobacterium tuberculosis</named-content>
title_short	Keto-Mycolic Acid-Dependent Pellicle Formation Confers Tolerance to Drug-Sensitive <named-content content-type="genus-species">Mycobacterium tuberculosis</named-content>
title_full	Keto-Mycolic Acid-Dependent Pellicle Formation Confers Tolerance to Drug-Sensitive <named-content content-type="genus-species">Mycobacterium tuberculosis</named-content>
title_fullStr	Keto-Mycolic Acid-Dependent Pellicle Formation Confers Tolerance to Drug-Sensitive <named-content content-type="genus-species">Mycobacterium tuberculosis</named-content>
title_full_unstemmed	Keto-Mycolic Acid-Dependent Pellicle Formation Confers Tolerance to Drug-Sensitive <named-content content-type="genus-species">Mycobacterium tuberculosis</named-content>
title_sort	keto-mycolic acid-dependent pellicle formation confers tolerance to drug-sensitive <named-content content-type="genus-species">mycobacterium tuberculosis</named-content>
publisher	American Society for Microbiology
publishDate	2013
url	https://doaj.org/article/0e4ca69911e645169334c63c251a3526
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Keto-Mycolic Acid-Dependent Pellicle Formation Confers Tolerance to Drug-Sensitive <named-content content-type="genus-species">Mycobacterium tuberculosis</named-content>

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