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A novel peptide interferes with Mycobacterium tuberculosis virulence and survival.

ABSTRACT: Tuberculosis (TB) is a huge global burden, with new and resistant strains emerging at an alarming rate, necessitating an urgent need for a new class of drug candidates. Here, we report that SL3, a novel 33-amino acid peptide, causes debilitating effects on mycobacterial morphology. Treatment with SL3 drastically inhibits the growth of Mycobacterium tuberculosis in vitro as well as in a pre-clinical mouse model for M.tb infection. Microarray analysis of SL3-expressing strain demonstrates wide-scale transcriptional disruption in M.tb. We therefore believe that SL3 and similar peptides may herald a new approach towards discovering new molecules for TB therapy.

SUBMITTER: Samuchiwal SK

PROVIDER: S-EPMC4208091 | biostudies-literature | 2014

REPOSITORIES: biostudies-literature

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A novel peptide interferes with Mycobacterium tuberculosis virulence and survival.

Samuchiwal Sachin Kumar SK Tousif Sultan S Singh Dhiraj Kumar DK Kumar Arun A Ghosh Anamika A Bhalla Kuhulika K Prakash Prem P Kumar Sushil S Trivedi Ashish Chandra AC Bhattacharyya Maitree M Das Gobardhan G Ranganathan Anand A

FEBS open bio 20140807

Tuberculosis (TB) is a huge global burden, with new and resistant strains emerging at an alarming rate, necessitating an urgent need for a new class of drug candidates. Here, we report that SL3, a novel 33-amino acid peptide, causes debilitating effects on mycobacterial morphology. Treatment with SL3 drastically inhibits the growth of Mycobacterium tuberculosis in vitro as well as in a pre-clinical mouse model for M.tb infection. Microarray analysis of SL3-expressing strain demonstrates wide-sca ...[more]

PMID: 25349777

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Project description:Nonribosomal peptide synthases produce short peptides in a manner that is distinct from classical mRNA-dependent ribosome-mediated translation. The Mycobacterium tuberculosis genome harbors a nonribosomal peptide synthase gene, nrp, which is part of a gene cluster proposed to be involved in the biosynthesis of isonitrile lipopeptides. Orthologous clusters are found in other slow-growing pathogenic mycobacteria and actinomycetes. To probe the role of the nrp gene in infection, we generated an nrp deletion mutant in M. tuberculosis H37Rv and tested its virulence in immunocompetent (C57BL/6) mice. The nrp mutant strain displayed lower initial growth rates in the lungs and a defective dissemination to the spleens of infected mice. Mice infected with the mutant strain also survived for twice as long as those infected with wild-type M. tuberculosis and, remarkably, showed subdued pathology, despite similar bacterial loads at later stages of infection. The differences in the course of infection between wild-type and nrp mutant strains were accompanied by distinct dynamics of the immune response. Most strikingly, the nrp mutant was highly attenuated in immunodeficient (SCID-, recombination activating 2 [RAG2]-, and gamma interferon [IFN-γ]-deficient) mice, suggesting that macrophages control the nrp mutant more efficiently than they control the wild-type strain. However, in the presence of IFN-γ, both strains were equally controlled. We propose that the nrp gene and its associated cluster are drivers of virulence during the early stages of infection.IMPORTANCE Over 10 million people developed tuberculosis (TB) in 2016, and over 1.8 million individuals succumbed to the disease. These numbers make TB the ninth leading cause of death worldwide and the leading cause from a single infectious agent. Therefore, finding novel therapeutic targets in Mycobacterium tuberculosis, the pathogen that causes most cases of human TB, is critical. In this study, we reveal a novel virulence factor in M. tuberculosis, the nrp gene. The lack of nrp highly attenuates the course of M. tuberculosis infection in the mouse model, which is particularly relevant in immune-deficient hosts. This is very relevant as TB is particularly incident in immune-suppressed individuals, such as HIV patients.

Dataset Information

A novel peptide interferes with Mycobacterium tuberculosis virulence and survival.

Publications

A novel peptide interferes with Mycobacterium tuberculosis virulence and survival.

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