Abstract
We have isolated and characterized a novel antibacterial peptide, CMB001, following an extensive screening effort of bacterial species isolated from diverse environmental sources. The bacterium that produces CMB001 is characterized as a Gram (+) bacillus sharing approximately 98.9% 16S rRNA sequence homology with its closest match, Paenibacillus kyungheensis. The molecule has been purified to homogeneity from its cell-free supernatant by a three-step preparative chromatography process. Based on its primary structure, CMB001 shares 81% identity with subtilin and 62% with nisin. CMB001 is active mainly against Gram-positive bacteria and Mycobacteriaceae but it is also active against certain Gram-negative bacteria, including multi-drug resistant Acinetobacter baumannii. It retains full antibacterial activity at neutral pH and displays a low propensity to select for resistance among targeted bacteria. Based on NMR and mass spectrometry, CMB001 forms a unique 3D-structure comprising of a compact backbone with one α-helix and two pseudo-α-helical regions. Screening the structure against the Protein Data Bank (PDB) revealed a partial match with nisin-lipid II (1WCO), but none of the lantibiotics with known structures showed significant structural similarity. Due to its unique structure, resistance profile, relatively broad spectrum and stability under physiological conditions, CMB001 is a promising drug candidate for evaluation in animal models of bacterial infection.
Highlights
For many decades, natural products were one of the major sources of new compounds or templates for discovery of novel drugs
We have shown that relative to nisin, CMB001 exhibits a much lower propensity to select resistance for S. aureus strains, including a MDR strain
We have shown that CMB001, at 4 × MIC fully eradicated biofilms pre-formed by either ATCC 29213 or MDR strains of S. aureus (Figure 4)
Summary
Natural products were one of the major sources of new compounds or templates for discovery of novel drugs. The majority of currently prescribed antibiotics are derived from natural sources. Based on a recent analysis, 78 antibiotics, or just over 48% of all approved antibiotics, are either natural products or were derived from them (Newman and Cragg, 2020). The benefits, challenges, and opportunities presented by antimicrobial peptides as drug candidates have been reviewed recently (Magana et al, 2020). Lantibiotics are naturally occurring, ribosomally synthesized cationic antimicrobial peptides produced by Gram-positive bacteria. These polycyclic peptides contain several posttranslationally modified amino acids: dehydroalanines, dehydrobutyrines and lanthionines
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