Novel Synthetic Polymyxin Variants Inspired by Newly Uncovered Natural Sequences Explored as Potential Antibiotics
The incidence of infections caused by multidrug-resistant bacterial agents has increased at an alarming rate worldwide. With the aim of identifying novel antimicrobial peptides (AMPs), we screened bacteria isolated from various environmental samples. Our hypothesis was that the sequence space of natural AMPs belonging to known AMP classes is far from saturation. We used a classical pipeline of…
An alarming increase in infections caused by multidrug-resistant bacterial agents has been observed globally. To discover novel antimicrobial peptides (AMPs), a research team screened bacteria from diverse environmental samples. The hypothesis was that natural AMPs within known classes have not yet achieved saturation in their sequence space.
The team employed a traditional methodology of bacterial cultivation, overlay assays, extraction, and fractionation to purify AMPs for identification. Through LC/MS analysis, the structure of AMPs isolated from a strain of Paenibacillus was elucidated, revealing a new subclass of polymyxins. These polymyxins possess three aliphatic residues within the cyclic C-terminal, and in certain instances, Ser replaces Thr at position A2.
Four distinct polymyxins, belonging to this new class but not identical to natural polymyxins, were synthesized and subjected to testing against 29 human pathogenic bacteria. Each candidate displayed an antibacterial spectrum distinct from colistin, with the most potent variant outperforming colistin against ten bacterial strains.
However, it showed reduced efficacy against three others. These findings indicate that screening natural bacterial isolates continues to offer the potential to design new antimicrobial peptide variants, without the risk of diminishing returns due to saturation.
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