Spider Venom Peptides as Potential Allosteric Inhibitors of Undecaprenyl Diphosphatase (UppP) from Acinetobacter baumannii: In Silico Identification and Structural Analysis

 

Spider Venom Peptides as Potential Allosteric Inhibitors of Undecaprenyl Diphosphatase (UppP) from Acinetobacter baumannii: In Silico Identification and Structural Analysis

Abstract

The antimicrobial resistance of Acinetobacter baumannii necessitates the development of novel therapeutic strategies targeting essential enzymes such as Undecaprenyl Pyrophosphate Phosphatase (UppP). This study explored spider venom peptides in silico as potential allosteric inhibitors of A. baumannii UppP. A systematic literature review was conducted to select eight α-helical peptides with reported anti-A. baumannii activity, followed by their computational physicochemical characterization. Three-dimensional models of A. baumannii UppP and the candidate peptides were generated, and a putative allosteric binding site was validated through molecular docking of a known inhibitor of the BacA homolog. The eight peptides were subsequently docked to this validated site using HADDOCK. Results revealed variable binding affinities; peptides LC-AMP-I1, Lycosin-II, and GK37 exhibited the most favorable HADDOCK scores and extensive interaction networks, consistent with their reported high antimicrobial potency. Other candidates, notably Lt-MAP2, showed low binding affinity but high predicted synergistic potential. These findings identify promising spider venom peptide candidates, suggesting dual (membrane disruption/UppP inhibition) or synergistic mechanisms of action, and validate UppP as a viable pharmacological target for peptide-based inhibitors.

Liscano, Y., Álvarez-Caballero, J. M., & Aragón-Muriel, A. (2026). Spider Venom Peptides as Potential Allosteric Inhibitors of Undecaprenyl Diphosphatase (UppP) from Acinetobacter baumannii: In Silico Identification and Structural Analysis. Toxins, 18(5). https://doi.org/10.3390/toxins18050210