The lipopeptide brevibacillin: A promising scaffold for the development of antimicrobials with tunable pharmacological properties and spectra of activity
Éric Biron
Faculty of Pharmacy, Université Laval and CHU de Québec Research Center, Quebec, Canada
Institute of Nutrition and Functional Foods, Université Laval, Quebec, Canada
Infectious Disease Research Center, Université Laval, Quebec, Canada
PROTEO, The Quebec Network for Research on Protein Function, Engineering, and Applications, Canada
With the increase and spread of antibiotic resistance, the development of innovative antimicrobials has become a global priority not only in human medicine but also in the agri-food and veterinary sectors. Antimicrobial peptides produced by bacteria such as bacteriocins and lipopeptides are promising alternatives to antibiotics. Among them, our team is interested in lipopeptides produced by Brevibacillus laterosporus like the lipotridecapeptides and ornicidines since they demonstrate high activity and original modes of action that are different from clinically used antibiotics. The lipotridecapeptide brevibacillin displays promising activity against several clinically relevant Gram-positive pathogens, including antibiotic-resistant strains such as methicillin-resistant Staphylococcus aureus (MRSA) and vancomycin-resistant Enterococcus (VRE). Despite its great potential, the use of brevibacillin is limited by the difficulties associated with its production, stability and cytotoxicity.
To overcome these limitations and improve the pharmacological profile of brevibacillin, our team used a medicinal chemistry approach and performed a structure-activity relationship investigation. A first study revealed that cationic amino acids are essential for brevibacillin’s activity against Gram-negative strains while the overall hydrophobicity plays an important role in the inhibition of Gram-positive bacteria and hemolysis. In another study, the substitution of the neutral Dhb residue at potition1 with a cationic amino acid increased the inhibitory activity toward Gram-negative bacteria and significantly reduced the hemolytic activity, but at the cost of less potency against Gram-positive strains. Finally, the combination of N-acyl substitution and a cationic amino acid at position 1 resulted in analogues exhibiting an extended spectrum of activity with minimal inhibitory concentration values in the low micromolar range against Gram-positive S. aureus, MRSA, Bacillus subtilis, Enterococcus faecium and Gram-negative Escherichia coli, Salmonella enterica, Klebsiella pneumoniae and Acinetobacter baumannii. The most active analogues identified in this study displayed enhanced killing kinetics and lower cytotoxicity compared to brevibacillin. With their enhanced synthetic accessibility, strong inhibitory activity, shifted or extended spectrum of action and improved selectivity index towards Gram-negative bacteria, these brevibacillin analogues are promising candidates for the development of new antimicrobials. Moreover, our investigation showed that the brevibacillin is very tolerant to modifications and a promising scaffold to develop antimicrobials with tunable spectrum of activity, physicochemical properties, proteolytic stability and pharmacological profile.