A novel peptide interferes with Mycobacterium tuberculosis virulence and survival

•The novel peptide SL3 is a strong binder of the virulence-determining protein ESAT-6.•SL3 caused debilitating effects on mycobacterial growth and morphology.•SL3 led to accelerated clearance of M.tb and lowered immune response in a pre-clinical mouse model.•Microarray analysis of the mutant strain demonstrated a wide-scale transcriptional disruption caused by SL3 in M.tb.

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.