Anti-Tuberculosis Activity of α-Helical Antimicrobial Peptides: De Novo Designed L- and D-Enantiomers Versus L- and D-LL37

Ziqing      Jiang; Michael      P. Higgins; James      Whitehurst; Kevin      O. Kisich; Martin      I. Voskuil; Robert      S. Hodges

doi:10.2174/092986611794578288

Abstract

With the emergence of multi-drug resistant (MDR) and extensively drug resistant (XDR) Mycobacterium tuberculosis (Mtb), new classes of anti-mycobacterial agents with very different modes of action compared to classical antibiotics, are urgently needed. In this study, a series of 26-residue, amphipathic α-helical antimicrobial peptides consisting of all D-amino acid residues and synthetic human L-LL37 (L-enantiomer) and D-LL37 (D-enantiomer) were investigated against M. tuberculosis susceptible strain (H37Rv) and a clinical multi-drug resistant strain (Vertulo). Minimal inhibitory concentrations (MICs) were determined through a peptide killing assay. D5, the most active analog against M. tuberculosis had a MIC value of 11.2 μM (35.2 μg/ml) against H37Rv strain and 15.6 μM (49 μg/ml) against the MDR strain. Peptide D1 had similar activity as D5 against the MDR strain (57 μg/mL), a 9-fold improvement in hemolytic activity and a 7.4-fold better therapeutic index compared to D5. Surprisingly, LL37 enantiomers showed little to no activity compared to the de-novo designed α-helical antimicrobial peptides.

Keywords: Antimicrobial peptides, Mycobacterium tuberculosis, hemolysis, all D-enantiomerAntimicrobial peptides, Mycobacterium tuberculosis, hemolysis, all D-enantiomer

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