A novel peptide interferes with Mycobacterium tuberculosis virulence and survival

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.

[1]  M. Horwitz,et al.  An Inhibitor of Exported Mycobacterium tuberculosis Glutamine Synthetase Selectively Blocks the Growth of Pathogenic Mycobacteria in Axenic Culture and in Human Monocytes: Extracellular Proteins as Potential Novel Drug Targets , 1999, The Journal of experimental medicine.

[2]  K. Natarajan,et al.  Phenylalanine-Rich Peptides Potently Bind ESAT6, a Virulence Determinant of Mycobacterium tuberculosis, and Concurrently Affect the Pathogen's Growth , 2009, PLoS ONE.

[3]  L. Kaer,et al.  T Cells from Programmed Death-1 Deficient Mice Respond Poorly to Mycobacterium tuberculosis Infection , 2011, PloS one.

[4]  Diogo F. Veiga,et al.  Linking the Transcriptional Profiles and the Physiological States of Mycobacterium tuberculosis during an Extended Intracellular Infection , 2012, PLoS pathogens.

[5]  Anamika Ghosh,et al.  A Three-Hybrid System to Probe In Vivo Protein-Protein Interactions: Application to the Essential Proteins of the RD1 Complex of M. tuberculosis , 2011, PloS one.

[6]  B. Samten,et al.  Mycobacterium tuberculosis ESX-1 system-secreted protein ESAT-6 but not CFP10 inhibits human T-cell immune responses. , 2009, Tuberculosis.

[7]  S. Cole,et al.  Bacterial Artificial Chromosome-Based Comparative Genomic Analysis Identifies Mycobacterium microti as a Natural ESAT-6 Deletion Mutant , 2002, Infection and Immunity.

[8]  熊礼宽,et al.  Mycobacterium , 1977, Bacteriological reviews.

[9]  B. Samten,et al.  ESAT-6 Inhibits Production of IFN-γ by Mycobacterium tuberculosis-Responsive Human T Cells1 , 2009, The Journal of Immunology.

[10]  L. Alksne.  Virulence as a target for antimicrobial chemotherapy , 2002, Expert opinion on investigational drugs.

[11]  G. Schoolnik,et al.  Comparative genomics of BCG vaccines by whole-genome DNA microarray. , 1999, Science.

[12]  S. Cole,et al.  Identification of variable regions in the genomes of tubercle bacilli using bacterial artificial chromosome arrays , 1999, Molecular microbiology.

[13]  Y. Singh,et al.  Synthesis and Selection of De Novo Proteins That Bind and Impede Cellular Functions of an Essential Mycobacterial Protein , 2006, Applied and Environmental Microbiology.

[14]  A. Arora,et al.  Mycobacterium tuberculosis H37Rv ESAT‐6–CFP‐10 complex formation confers thermodynamic and biochemical stability , 2006, The FEBS journal.

[15]  G. Mahairas,et al.  Molecular analysis of genetic differences between Mycobacterium bovis BCG and virulent M. bovis , 1996, Journal of bacteriology.

[16]  M. Chase,et al.  Mutually dependent secretion of proteins required for mycobacterial virulence. , 2005, Proceedings of the National Academy of Sciences of the United States of America.

[17]  D. Sherman,et al.  Tuberculous Granuloma Formation Is Enhanced by a Mycobacterium Virulence Determinant , 2004, PLoS biology.

[18]  S. Cole,et al.  ESAT-6 from Mycobacterium tuberculosis Dissociates from Its Putative Chaperone CFP-10 under Acidic Conditions and Exhibits Membrane-Lysing Activity , 2007, Journal of bacteriology.

[19]  P. Sharma,et al.  ESAT6 differentially inhibits IFN‐γ‐inducible class II transactivator isoforms in both a TLR2‐dependent and ‐independent manner , 2012, Immunology and cell biology.

[20]  B. Barrell,et al.  Deciphering the biology of Mycobacterium tuberculosis from the complete genome sequence , 1998, Nature.

[21]  I. Smith,et al.  Mycobacterium tuberculosis Pathogenesis and Molecular Determinants of Virulence , 2003, Clinical Microbiology Reviews.

[22]  Alex E. Lash,et al.  Gene Expression Omnibus: NCBI gene expression and hybridization array data repository , 2002, Nucleic Acids Res..

[23]  K. Derbyshire,et al.  The RD1 virulence locus of Mycobacterium tuberculosis regulates DNA transfer in Mycobacterium smegmatis. , 2004, Proceedings of the National Academy of Sciences of the United States of America.

[24]  V. Singh,et al.  Genome-wide transcriptional profiling of the response of Staphylococcus aureus to cell-wall-active antibiotics reveals a cell-wall-stress stimulon. , 2003, Microbiology.

[25]  Christopher M. Sassetti,et al.  Genetic requirements for mycobacterial survival during infection , 2003, Proceedings of the National Academy of Sciences of the United States of America.

[26]  Jingjing Xu,et al.  The CFP10/ESAT6 complex of Mycobacterium tuberculosis may function as a regulator of macrophage cell death at different stages of tuberculosis infection. , 2012, Medical hypotheses.

[27]  Li Huixing,et al.  Interaction of Mycobacterium tuberculosis ESAT-6 protein with ADAM9 protein , 2011 .

[28]  S. Gordon,et al.  Conclusive Evidence That the Major T-cell Antigens of theMycobacterium tuberculosis Complex ESAT-6 and CFP-10 Form a Tight, 1:1 Complex and Characterization of the Structural Properties of ESAT-6, CFP-10, and the ESAT-6·CFP-10 Complex , 2002, The Journal of Biological Chemistry.

[29]  Sarman Singh,et al.  Genome-wide Analysis of the Host Intracellular Network that Regulates Survival of Mycobacterium tuberculosis , 2010, Cell.

[30]  S. Morris,et al.  The ESAT6 protein of Mycobacterium tuberculosis induces apoptosis of macrophages by activating caspase expression , 2007, Cellular microbiology.

[31]  E. Rubin,et al.  Genes required for mycobacterial growth defined by high density mutagenesis , 2003, Molecular microbiology.