Molecular engineering of antimicrobial peptides: microbial targets, peptide motifs and translation opportunities

Abstract

The global public health threat of antimicrobial resistance has led the scientific community to highly engage into research on alternative strategies to the traditional small molecule therapeutics. Here, we review one of the most popular alternatives amongst basic and applied research scientists, synthetic antimicrobial peptides. The ease of peptide chemical synthesis combined with emerging engineering principles and potent broad-spectrum activity, including against multidrug-resistant strains, has motivated intense scientific focus on these compounds for the past decade. This global effort has resulted in significant advances in our understanding of peptide antimicrobial activity at the molecular scale. Recent evidence of molecular targets other than the microbial lipid membrane, and efforts towards consensus antimicrobial peptide motifs, have supported the rise of molecular engineering approaches and design tools, including machine learning. Beyond molecular concepts, supramolecular chemistry has been lately added to the debate; and helped unravel the impact of peptide self-assembly on activity, including on biofilms and secondary targets, while providing new directions in pharmaceutical formulation through taking advantage of peptide self-assembled nanostructures. We argue that these basic research advances constitute a solid basis for promising industry translation of rationally designed synthetic peptide antimicrobials, not only as novel drugs against multidrug-resistant strains but also as components of emerging antimicrobial biomaterials. This perspective is supported by recent developments of innovative peptide-based and peptide-carrier nanobiomaterials that we also review.

Keywords: Antimicrobial peptides; Antimicrobial resistance; Biomaterials; Molecular engineering; Molecular self-assembly; Nanotechnology; Peptide-target interactions.

Fig. 1

Main molecular mechanisms of action and resistance for marketed antibiotics. Modified from Wright

Fig. 2

Membrane disruption molecular models and some intracellular targets of AMPs. Reproduced from Mookherjee et al. . Copyright © 2020, Springer Nature Limited

Fig. 3

Main models of membrane disruption by amyloid oligomers. Reproduced from Dharmadana et al. . Copyright © 2017, The Royal Society Publishing

Fig. 4

Mechanisms of bacterial resistance to AMPs. (1) Extracellular proteases perform proteolytic degradation; (2) sequestration can occur by extracellular matrix or extracellular proteins; (3) alanylated teichoic acids create electrostatic repulsion; (4) aminoacylated peptidoglycan also create electrostatic repulsion; (5) lack of lipid II-binding AMPs by pentapeptide alteration; (6) AMPs rejection by efflux pumps; (7) proteolytic cleavage by cytosolic protease after uptake by transporters; (8) sequestration or steric hindrance by O-antigen of LPS; (9) amine compound-added lipid A creates electrostatic repulsion; (10) lipid A acylation creates increased rigidity. Figure modified from Joo et al.

Fig. 5

Three-stage de novo peptide design workflow diagram. (1) design inputs and sequence selection; (2) fold specificity; (3) approximate binding affinity. Modified from Smadbeck et al.