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 M). 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.

Laterosporulin10: a novel defensin like Class IId bacteriocin from Brevibacillus sp. strain SKDU10 with inhibitory activity against microbial pathogens

“…However, among the various conventional indicator strains, laterosporulin10 effectively inhibited S. aureus (Fig. 2a), a bacterial strain considered to be a surrogate bacterium for the prediction of antimicrobial peptide activity against the Mtb H37Rv strain (Ramón-García et al, 2013). Therefore, we selected laterosporulin10 to test antimicrobial activity against the pathogenic M. tuberculosis H37Rv strain.…”

Combined Bioinformatic and Rational Design Approach To Develop Antimicrobial Peptides against Mycobacterium tuberculosis

“…The database contained both natural, broadly active AMPs and synthetic AMPs screened specifically against M. tuberculosis. The majority of the synthetic peptides were identified in a single screen performed by Ramon-Garcia et al (9). The peptides identified by Ramon-Garcia et al skew the database toward increased hydrophobicity and positive charge; however, these properties were shown by those authors to correlate with increased antimicrobial potency.…”

“…Transport of hydrophilic molecules is mediated by outer membranes proteins, of which few are known and even fewer are characterized (6)(7)(8). Despite these daunting membrane properties, AMPs with activity against M. tuberculosis have been reported (9)(10)(11)(12).…”

The antimicrobial effect of colistin methanesulfonate on Mycobacterium tuberculosis in vitro

“…antagonises the effect of cationic antimicrobial peptides [43,44] (this might not apply to polymyxins [45]); (4) it has been proposed that polymyxins also induce cell death through hydroxyl radical production i.e., Fenton reaction [46], and the presence of catalase in OADC would antagonise this mechanism of action.…”