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Biomaterials

Biomaterials - Poster Session C

Poster D1 - Machine learning approach to designing antimicrobial biomaterials

Friday, October 25, 2024
10:00 AM - 11:00 AM EST
Location: Exhibit Hall E, F & G

Introduction:  Antibiotic drug resistance is approaching a state of crisis throughout the world. The inadequacy of the current antibiotic pipeline and the lack of agents with novel mechanisms of action motivate this project to accelerate the discovery of next-generation antibiotic systems. Our research, which spans the fields of microbiology, biochemistry, and pharmaceuticals, is focused on peptoids, a relatively new class of compounds. These compounds offer a potential solution to the challenges faced by peptide-based antimicrobials, which are susceptible to in vivo proteolytic degradation. Peptoids are polymerized N-substituted glycine with side chains attached to the N of the backbone amide, a unique feature that prevents enzymatic degradation and denaturation. This isomerization from Cα to N in peptoids enhances biostability and bioavailability in host environments and underscores the importance of multidisciplinary collaboration in advancing scientific research.
Previous work on peptoids has shown that peptoids self-assemble and exhibit antimicrobial activity against bacterial and viral pathogens, the primary cause of hospital-acquired infections exhibiting high virulence and multidrug resistance. These ten peptoids are also active against tested viruses and fungi. Previous work also demonstrates that the peptoid's apparent or effective 'hydrophobicity' is a crucial determinant of antibacterial activity. For example, chemical modifications (addition of bromine) or the alkyl tail allow shorter peptoids (7-mers) to have increased activity. Without such modifications, a 7-mer peptoid would otherwise have weak antibacterial activity. In this project, we will focus on 7-mers to reduce the experimental costs of peptoid synthesis and to increase yields (compared to longer-length sequences).

Materials and

Methods:  Our approach has been to build the molecular structure of peptoids using an automated Python script that uses three-dimensional structures of the peptoid monomers (Nlys, Nspe, and NspBr) as templates to create a 7-mer. The force field parameters will be derived from the ligand utility available in CHARMM-GUI (CHARMM Graphical User Interface), a web-based graphical user interface. Using a recently developed in-house Python script, we will circumvent this problem. I will prepare the complete library of 2187 structures and their force field parameters. Next, we computed the hydropathy of the peptoid structure on a 0-10 scale. The Nangia group recently developed a Protocol for Assigning a Residue's Character on the Hydropathy (PARCH) scale that adopts a holistic approach to assigning the hydropathy of a residue. The parch scale evaluates the collective response of the water molecules in the molecule's first hydration shell to increasing temperatures. A residue that loses water readily has low parch vale (0-1) versus a residue that retains water (>2). The PARCH calculations were performed for peptoids and rank-ordered from most to least hydrophilic.

Results, Conclusions, and Discussions: Results

The hydropathy analysis of the peptoid structures revealed a strong dependence on the net charge on the peptoid for sequences bearing one or more Nlys building blocks, making the peptoids hydrophilic.  Such peptoids are expected not to self-assemble. On the other hand, the lack of Nlys made the peptoids hydrophobic, which is unsuitable for use as antimicrobial biomaterials. We show that for 7-mer peptoids, composed of Nlys, Nspe, and NspBr, the optimal charge for antimicrobial activity is +2 or +3.     

Discussion

This study evaluates the properties of peptoids, which are biomimetic materials similar to antimicrobial peptides (AMPs). Most mammalian and other organisms secrete antimicrobial peptides (AMPs) to defend against bacterial pathogens.8,9 The AMPs are cationic amphiphiles that selectively bind and permeabilize the pathogens' anionic cell membranes, while not affecting the zwitterionic host cell membranes. In vivo efficacy of native AMPs is high; however, even after decades of research AMP-based therapeutics have seen limited success largely due to challenges of proteolytic degradation and reduced bioavailability.10 Peptoids, in contrast, circumvent the shortfalls of AMPs and also have four clear advantages over them: (i) easy solid phase synthesis using conventional peptide synthesis equipment; (ii) multiple building blocks (i.e., any chemical functionality available as a primary amine can be incorporated via a submonomer synthetic method); (iii) relatively low cost; (iv) lower proteolytic degradation and higher bioavailability. In sum, the advantages of peptoids outweigh those of any other peptidomimetic systems, e.g., β-peptides, β-peptoids, cyclo-peptoids, oligoureas, and oligo(phenylene ethynylenes). Notably, the self-assembled morphologies of isomeric peptoids and peptides differ. In other words, peptoids have substantially distinct chemical differences and biological activity compared to their peptide analogs, making them even better candidates for antimicrobial activity than AMPs.

Conclusions

The study shows that peptoids have several advantages compared to peptides in their use as antimicrobial agents. However, to design effective peptoids, we need to optimize the amount of charge on peptoids and their length. In this study of 7-mer peptoids, the optimal charge for antimicrobial activity is +2 or +3.

Acknowledgements (Optional):