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bioRxiv · 10.1101/2023.10.19.563059

Mining the heparinome for cryptic antimicrobial peptides that selectively kill gram-negative bacteria

Sandin Garcia, D.·Valle, J.·Gomez, J.·Comas, L.·Larrosa, M. N.·Gonzalez, J. J.·Jimenez, M. A.·Andreu, D.·Torrent, M.
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Abstract

Glycosaminoglycan (GAG)-binding proteins regulating essential processes such as cell growth and migration are essential for cell homeostasis. As both GAGs and the lipid A disaccharide core of gram-negative bacteria contain negatively charged disaccharide units, we hypothesized that GAG-binding proteins could also recognize LPS and enclose cryptic antibiotic motifs. Here, we report novel antimicrobial peptides (AMPs) derived from heparin-binding proteins (HBPs), with specific activity against gram-negative bacteria and high LPS binding. We used computational tools to locate antimicrobial regions in 82% of HBPs, most of those colocalizing with putative heparin binding sites. To validate these results, we synthesized five candidates [HBP1-5] that showed remarkable activity against gram-negative bacteria, as well as a strong correlation between heparin and LPS binding. Structural characterization of these AMPs shows that heparin or LPS recognition promotes a conformational arrangement that favors binding. Among all analogs, HBP-5 displayed the highest affinity for both heparin and LPS, with antimicrobial activities against gram-negative bacteria at the nanomolar range. These results suggest that GAG-binding proteins are involved in LPS recognition, which allows them to act also as antimicrobial proteins. Some of the peptides reported here, particularly HBP-5, constitute a new class of AMPs with specific activity against gram-negative bacteria.

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Sandin Garcia, D., Valle, J., Gomez, J., Comas, L., Larrosa, M. N., Gonzalez, J. J., Jimenez, M. A., Andreu, D., Torrent, M.. 2023-10-22. Mining the heparinome for cryptic antimicrobial peptides that selectively kill gram-negative bacteria. https://doi.org/10.1101/2023.10.19.563059

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