title: Anti-tuberculosis activity of α-helical antimicrobial peptides: de novo designed L- and D-enantiomers versus L- and D-LL-37.
abstract: With the emergence of multi-drug resistant (MDR) and extensively drug resistant (XDR) Mycobacterium tuberculosis (Mtb), a new class of antimycobacterial 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.
authors.affiliation: Department of Biochemistry & Molecular Genetics, University of Colorado, School of Medicine, Aurora, CO 80045, USA.
authors.forename: Ziqing
authors.initials: Z
authors.lastname: Jiang
authors.forename: Michael P
authors.initials: MP
authors.lastname: Higgins
authors.forename: James
authors.initials: J
authors.lastname: Whitehurst
authors.forename: Kevin O
authors.initials: KO
authors.lastname: Kisich
authors.forename: Martin I
authors.initials: MI
authors.lastname: Voskuil
authors.forename: Robert S
authors.initials: RS
authors.lastname: Hodges
mesh_terms: D000595:Amino Acid Sequence; D019943:Amino Acid Substitution; D023181:Antimicrobial Cationic Peptides; D000995:Antitubercular Agents / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D054804:Cathelicidins / Q000138:chemical synthesis / Q000737:chemistry* / Q000235:genetics / Q000494:pharmacology*; D015195:Drug Design; D018432:Drug Resistance, Multiple; D006461:Hemolysis / Q000187:drug effects; D006801:Humans; D057927:Hydrophobic and Hydrophilic Interactions; D008826:Microbial Sensitivity Tests; D008969:Molecular Sequence Data; D009169:Mycobacterium tuberculosis / Q000187:drug effects; D017433:Protein Structure, Secondary; D013237:Stereoisomerism; D013329:Structure-Activity Relationship
chemical_list: D023181:Antimicrobial Cationic Peptides; D000995:Antitubercular Agents; D054804:Cathelicidins