title: Targeting Mycobacterium tuberculosis and other microbial pathogens using improved synthetic antibacterial peptides.
abstract: The lack of effective therapies for treating tuberculosis (TB) is a global health problem. While Mycobacterium tuberculosis is notoriously resistant to most available antibiotics, we identified synthetic short cationic antimicrobial peptides that were active at low micromolar concentrations (less than 10 μM). These small peptides (averaging 10 amino acids) had remarkably broad spectra of antimicrobial activities against both bacterial and fungal pathogens and an indication of low cytotoxicity. In addition, their antimicrobial activities displayed various degrees of species specificity that were not related to taxonomy. For example, Candida albicans and Staphylococcus aureus were the best surrogates to predict peptide activity against M. tuberculosis, while Mycobacterium smegmatis was a poor surrogate. Principle component analysis of activity spectrum profiles identified unique features associated with activity against M. tuberculosis that reflect their distinctive amino acid composition; active peptides were more hydrophobic and cationic, reflecting increased tryptophan with compensating decreases in valine and other uncharged amino acids and increased lysine. These studies provide foundations for development of cationic antimicrobial peptides as potential new therapeutic agents for TB treatment.
authors.affiliation: Department of Microbiology and Immunology, University of British Columbia, Vancouver, Canada.
authors.forename: Santiago
authors.initials: S
authors.lastname: Ramón-García
authors.forename: Ralf
authors.initials: R
authors.lastname: Mikut
authors.forename: Carol
authors.initials: C
authors.lastname: Ng
authors.forename: Serge
authors.initials: S
authors.lastname: Ruden
authors.forename: Rudolf
authors.initials: R
authors.lastname: Volkmer
authors.forename: Markus
authors.initials: M
authors.lastname: Reischl
authors.forename: Kai
authors.initials: K
authors.lastname: Hilpert
authors.forename: Charles J
authors.initials: CJ
authors.lastname: Thompson
mesh_terms: D000595:Amino Acid Sequence; D023181:Antimicrobial Cationic Peptides / Q000138:chemical synthesis / Q000494:pharmacology*; D000995:Antitubercular Agents / Q000138:chemical synthesis / Q000494:pharmacology*; D002176:Candida albicans / Q000187:drug effects* / Q000254:growth & development; D057927:Hydrophobic and Hydrophilic Interactions; D008826:Microbial Sensitivity Tests; D008954:Models, Biological; D008969:Molecular Sequence Data; D020102:Mycobacterium smegmatis / Q000187:drug effects / Q000254:growth & development; D009169:Mycobacterium tuberculosis / Q000187:drug effects* / Q000254:growth & development; D019151:Peptide Library; D025341:Principal Component Analysis; D013045:Species Specificity; D013211:Staphylococcus aureus / Q000187:drug effects* / Q000254:growth & development; D013329:Structure-Activity Relationship
chemical_list: D023181:Antimicrobial Cationic Peptides; D000995:Antitubercular Agents; D019151:Peptide Library