Novel Synthetic Polymyxin Variants Inspired by Newly Uncovered Natural Sequences Explored as Potential Antibiotics
- 1Synthetic and Systems Biology Unit, Institute of Biochemistry, Hun-Ren Biological Research Centre, Szeged, Hungary
Abstract
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 bacterial culturing, overlay assays, extraction and fractionation to purify AMPs for identification. Using LC/MS analysis, the structure of AMPs isolated from a strain of Paenibacillus was narrowed down and a new subclass of polymyxins was uncovered. These harbor three aliphatic residues within the cyclic C-terminal, and in certain cases Ser replaces Thr at position A2. Four discrete polymyxins fitting the new class, but not identical to the natural polymyxins were synthesized and tested against 29 human pathogenic bacteria. Each displayed an antibacterial spectrum different from that of colistin, with the best candidate surpassing it in potency against ten bacterial strains, but underperforming against three others. These results demonstrate that current screening of natural bacterial isolates can still permit the design of novel antimicrobial peptide variants without the substantial threat of diminishing returns.
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BibTeX
@misc{ajibola2026novel,
title = {{Novel Synthetic Polymyxin Variants Inspired by Newly Uncovered Natural Sequences Explored as Potential Antibiotics}},
author = {W. Ajibola and R. Tengolics and B. Mahmood and A. Marton and E. Hunyadi-Gulyas and C. Vizler and J. Soki and Z. Darula and T. Feher},
howpublished = {bioRxiv},
year = {2026},
month = sep,
doi = {10.64898/2026.09.25.754415},
url = {https://www.biorxiv.org/content/10.64898/2026.09.25.754415v1},
note = {CC BY-NC-ND},
}
RIS
TY - UNPB
TI - Novel Synthetic Polymyxin Variants Inspired by Newly Uncovered Natural Sequences Explored as Potential Antibiotics
AU - W. Ajibola
AU - R. Tengolics
AU - B. Mahmood
AU - A. Marton
AU - E. Hunyadi-Gulyas
AU - C. Vizler
AU - J. Soki
AU - Z. Darula
AU - T. Feher
PY - 2026
DA - 2026/09/25
PB - bioRxiv
DO - 10.64898/2026.09.25.754415
UR - https://www.biorxiv.org/content/10.64898/2026.09.25.754415v1
AB - 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 bacterial culturing, overlay assays, extraction and fractionation to purify AMPs for identification. Using LC/MS analysis, the structure of AMPs isolated from a strain of Paenibacillus was narrowed down and a new subclass of polymyxins was uncovered. These harbor three aliphatic residues within the cyclic C-terminal, and in certain cases Ser replaces Thr at position A2. Four discrete polymyxins fitting the new class, but not identical to the natural polymyxins were synthesized and tested against 29 human pathogenic bacteria. Each displayed an antibacterial spectrum different from that of colistin, with the best candidate surpassing it in potency against ten bacterial strains, but underperforming against three others. These results demonstrate that current screening of natural bacterial isolates can still permit the design of novel antimicrobial peptide variants without the substantial threat of diminishing returns.
ER -