Genome-wide identification of essential genes in Mycobacterium intracellulare by transposon sequencing — Implication for metabolic remodeling

Yoshitaka Tateishi; Yusuke Minato; Anthony D. Baughn; Hiroaki Ohnishi; Akihito Nishiyama; Yuriko Ozeki; Sohkichi Matsumoto

doi:10.1038/s41598-020-62287-2

Genome-wide identification of essential genes in Mycobacterium intracellulare by transposon sequencing — Implication for metabolic remodeling

Yoshitaka Tateishi, Yusuke Minato, Anthony D. Baughn, Hiroaki Ohnishi, Akihito Nishiyama, Yuriko Ozeki, Sohkichi Matsumoto

Microbiology

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Abstract

The global incidence of the human nontuberculous mycobacteria (NTM) disease is rapidly increasing. However, knowledge of gene essentiality under optimal growth conditions and conditions relevant to the natural ecology of NTM, such as hypoxia, is lacking. In this study, we utilized transposon sequencing to comprehensively identify genes essential for growth in Mycobacterium intracellulare. Of 5126 genes of M. intracellulare ATCC13950, 506 genes were identified as essential genes, of which 280 and 158 genes were shared with essential genes of M. tuberculosis and M. marinum, respectively. The shared genes included target genes of existing antituberculous drugs including SQ109, which targets the trehalose monomycolate transporter MmpL3. From 175 genes showing decreased fitness as conditionally essential under hypoxia, preferential carbohydrate metabolism including gluconeogenesis, glyoxylate cycle and succinate production was suggested under hypoxia. Virulence-associated genes including proteasome system and mycothiol redox system were also identified as conditionally essential under hypoxia, which was further supported by the higher effective suppression of bacterial growth under hypoxia compared to aerobic conditions in the presence of these inhibitors. This study has comprehensively identified functions essential for growth of M. intracellulare under conditions relevant to the host environment. These findings provide critical functional genomic information for drug discovery.

Original language	English (US)
Article number	5449
Journal	Scientific reports
Volume	10
Issue number	1
DOIs	https://doi.org/10.1038/s41598-020-62287-2
State	Published - Dec 1 2020

Bibliographical note

Funding Information:
The authors appreciate Dr. Torin Weisbrod and Dr. William R. Jacobs, Jr. (Albert Einstein College of Medicine, USA) for kindly providing mycobacterial phage phAE180. The authors appreciate Dr. Helena Boshoff (National Institute of Health, USA) for kindly providing SQ109 compound. The authors appreciate Ms. Shaban Amina Kaboso for proofreading the manuscript. This work was supported by Grants-in-Aid for Scientific Research (grant number 18K08172 to Yoshitaka Tateishi) from the Ministry of Health, Labour and Welfare and the National Institute of Allergy and Infectious Diseases/National Institute of Health grant (grant number AI123146 to Anthony D. Baughn). This work was also supported by grants from the Japanese Ministry of Education, Culture, Sports, Science, and Technology, the Ministry of Health and the Research Program on Emerging and Reemerging Infectious Disease from the Japan Agency for Medical Research and Development, AMED.

Publisher Copyright:
© 2020, The Author(s).

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title = "Genome-wide identification of essential genes in Mycobacterium intracellulare by transposon sequencing — Implication for metabolic remodeling",

abstract = "The global incidence of the human nontuberculous mycobacteria (NTM) disease is rapidly increasing. However, knowledge of gene essentiality under optimal growth conditions and conditions relevant to the natural ecology of NTM, such as hypoxia, is lacking. In this study, we utilized transposon sequencing to comprehensively identify genes essential for growth in Mycobacterium intracellulare. Of 5126 genes of M. intracellulare ATCC13950, 506 genes were identified as essential genes, of which 280 and 158 genes were shared with essential genes of M. tuberculosis and M. marinum, respectively. The shared genes included target genes of existing antituberculous drugs including SQ109, which targets the trehalose monomycolate transporter MmpL3. From 175 genes showing decreased fitness as conditionally essential under hypoxia, preferential carbohydrate metabolism including gluconeogenesis, glyoxylate cycle and succinate production was suggested under hypoxia. Virulence-associated genes including proteasome system and mycothiol redox system were also identified as conditionally essential under hypoxia, which was further supported by the higher effective suppression of bacterial growth under hypoxia compared to aerobic conditions in the presence of these inhibitors. This study has comprehensively identified functions essential for growth of M. intracellulare under conditions relevant to the host environment. These findings provide critical functional genomic information for drug discovery.",

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Genome-wide identification of essential genes in Mycobacterium intracellulare by transposon sequencing — Implication for metabolic remodeling

Abstract

Bibliographical note

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