Targeting Drug-Sensitive and -Resistant Strains of <named-content content-type="genus-species">Mycobacterium tuberculosis</named-content> by Inhibition of Src Family Kinases Lowers Disease Burden and Pathology

ABSTRACT In view of emerging drug resistance among bacterial pathogens, including Mycobacterium tuberculosis, the development of novel therapeutic strategies is increasingly being sought. A recent paradigm in antituberculosis (anti-TB) drug development is to target the host molecules that are crucia...

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Autores principales:	Pallavi Chandra, R. S. Rajmani, Garima Verma, Neel Sarovar Bhavesh, Dhiraj Kumar
Formato:	article
Lenguaje:	EN
Publicado:	American Society for Microbiology 2016
Materias:	adjunct therapy host-directed therapy MDR-TB XDR-TB Microbiology QR1-502
Acceso en línea:	https://doaj.org/article/6377b2d672b64984b583c2174a7bc2e4
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spelling	oai:doaj.org-article:6377b2d672b64984b583c2174a7bc2e42021-11-15T15:21:21ZTargeting Drug-Sensitive and -Resistant Strains of <named-content content-type="genus-species">Mycobacterium tuberculosis</named-content> by Inhibition of Src Family Kinases Lowers Disease Burden and Pathology10.1128/mSphere.00043-152379-5042https://doaj.org/article/6377b2d672b64984b583c2174a7bc2e42016-04-01T00:00:00Zhttps://journals.asm.org/doi/10.1128/mSphere.00043-15https://doaj.org/toc/2379-5042ABSTRACT In view of emerging drug resistance among bacterial pathogens, including Mycobacterium tuberculosis, the development of novel therapeutic strategies is increasingly being sought. A recent paradigm in antituberculosis (anti-TB) drug development is to target the host molecules that are crucial for intracellular survival of the pathogen. We previously showed the importance of Src tyrosine kinases in mycobacterial pathogenesis. Here, we report that inhibition of Src significantly reduced survival of H37Rv as well as multidrug-resistant (MDR) and extremely drug-resistant (XDR) strains of M. tuberculosis in THP-1 macrophages. Src inhibition was also effective in controlling M. tuberculosis infection in guinea pigs. In guinea pigs, reduced M. tuberculosis burden due to Src inhibition also led to a marked decline in the disease pathology. In agreement with the theoretical framework of host-directed approaches against the pathogen, Src inhibition was equally effective against an XDR strain in controlling infection in guinea pigs. We propose that Src inhibitors could be developed into effective host-directed anti-TB drugs, which could be indiscriminately used against both drug-sensitive and drug-resistant strains of M. tuberculosis. IMPORTANCE The existing treatment regimen for tuberculosis (TB) suffers from deficiencies like high doses of antibiotics, long treatment duration, and inability to kill persistent populations in an efficient manner. Together, these contribute to the emergence of drug-resistant tuberculosis. Recently, several host factors were identified which help intracellular survival of Mycobacterium tuberculosis within the macrophage. These factors serve as attractive targets for developing alternate therapeutic strategies against M. tuberculosis. This strategy promises to be effective against drug-resistant strains. The approach also has potential to considerably lower the risk of emergence of new drug-resistant strains. We explored tyrosine kinase Src as a host factor exploited by virulent M. tuberculosis for intracellular survival. We show that Src inhibition can effectively control tuberculosis in infected guinea pigs. Moreover, Src inhibition ameliorated TB-associated pathology in guinea pigs. Thus, Src inhibitors have strong potential to be developed as possible anti-TB drugs.Pallavi ChandraR. S. RajmaniGarima VermaNeel Sarovar BhaveshDhiraj KumarAmerican Society for Microbiologyarticleadjunct therapyhost-directed therapyMDR-TBXDR-TBMicrobiologyQR1-502ENmSphere, Vol 1, Iss 2 (2016)
institution	DOAJ
collection	DOAJ
language	EN
topic	adjunct therapy host-directed therapy MDR-TB XDR-TB Microbiology QR1-502
spellingShingle	adjunct therapy host-directed therapy MDR-TB XDR-TB Microbiology QR1-502 Pallavi Chandra R. S. Rajmani Garima Verma Neel Sarovar Bhavesh Dhiraj Kumar Targeting Drug-Sensitive and -Resistant Strains of <named-content content-type="genus-species">Mycobacterium tuberculosis</named-content> by Inhibition of Src Family Kinases Lowers Disease Burden and Pathology
description	ABSTRACT In view of emerging drug resistance among bacterial pathogens, including Mycobacterium tuberculosis, the development of novel therapeutic strategies is increasingly being sought. A recent paradigm in antituberculosis (anti-TB) drug development is to target the host molecules that are crucial for intracellular survival of the pathogen. We previously showed the importance of Src tyrosine kinases in mycobacterial pathogenesis. Here, we report that inhibition of Src significantly reduced survival of H37Rv as well as multidrug-resistant (MDR) and extremely drug-resistant (XDR) strains of M. tuberculosis in THP-1 macrophages. Src inhibition was also effective in controlling M. tuberculosis infection in guinea pigs. In guinea pigs, reduced M. tuberculosis burden due to Src inhibition also led to a marked decline in the disease pathology. In agreement with the theoretical framework of host-directed approaches against the pathogen, Src inhibition was equally effective against an XDR strain in controlling infection in guinea pigs. We propose that Src inhibitors could be developed into effective host-directed anti-TB drugs, which could be indiscriminately used against both drug-sensitive and drug-resistant strains of M. tuberculosis. IMPORTANCE The existing treatment regimen for tuberculosis (TB) suffers from deficiencies like high doses of antibiotics, long treatment duration, and inability to kill persistent populations in an efficient manner. Together, these contribute to the emergence of drug-resistant tuberculosis. Recently, several host factors were identified which help intracellular survival of Mycobacterium tuberculosis within the macrophage. These factors serve as attractive targets for developing alternate therapeutic strategies against M. tuberculosis. This strategy promises to be effective against drug-resistant strains. The approach also has potential to considerably lower the risk of emergence of new drug-resistant strains. We explored tyrosine kinase Src as a host factor exploited by virulent M. tuberculosis for intracellular survival. We show that Src inhibition can effectively control tuberculosis in infected guinea pigs. Moreover, Src inhibition ameliorated TB-associated pathology in guinea pigs. Thus, Src inhibitors have strong potential to be developed as possible anti-TB drugs.
format	article
author	Pallavi Chandra R. S. Rajmani Garima Verma Neel Sarovar Bhavesh Dhiraj Kumar
author_facet	Pallavi Chandra R. S. Rajmani Garima Verma Neel Sarovar Bhavesh Dhiraj Kumar
author_sort	Pallavi Chandra
title	Targeting Drug-Sensitive and -Resistant Strains of <named-content content-type="genus-species">Mycobacterium tuberculosis</named-content> by Inhibition of Src Family Kinases Lowers Disease Burden and Pathology
title_short	Targeting Drug-Sensitive and -Resistant Strains of <named-content content-type="genus-species">Mycobacterium tuberculosis</named-content> by Inhibition of Src Family Kinases Lowers Disease Burden and Pathology
title_full	Targeting Drug-Sensitive and -Resistant Strains of <named-content content-type="genus-species">Mycobacterium tuberculosis</named-content> by Inhibition of Src Family Kinases Lowers Disease Burden and Pathology
title_fullStr	Targeting Drug-Sensitive and -Resistant Strains of <named-content content-type="genus-species">Mycobacterium tuberculosis</named-content> by Inhibition of Src Family Kinases Lowers Disease Burden and Pathology
title_full_unstemmed	Targeting Drug-Sensitive and -Resistant Strains of <named-content content-type="genus-species">Mycobacterium tuberculosis</named-content> by Inhibition of Src Family Kinases Lowers Disease Burden and Pathology
title_sort	targeting drug-sensitive and -resistant strains of <named-content content-type="genus-species">mycobacterium tuberculosis</named-content> by inhibition of src family kinases lowers disease burden and pathology
publisher	American Society for Microbiology
publishDate	2016
url	https://doaj.org/article/6377b2d672b64984b583c2174a7bc2e4
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Targeting Drug-Sensitive and -Resistant Strains of <named-content content-type="genus-species">Mycobacterium tuberculosis</named-content> by Inhibition of Src Family Kinases Lowers Disease Burden and Pathology

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