A Critical Evaluation of Random Copolymer Mimesis of Homogeneous Antimicrobial Peptides

Abstract

Polymeric synthetic mimics of antimicrobial peptides (SMAMPs) have recently demonstrated similar antimicrobial activity as natural antimicrobial peptides (AMPs) from innate immunity. This is surprising, since polymeric SMAMPs are heterogeneous in terms of chemical structure (random sequence) and conformation (random coil), in contrast to defined amino acid sequence and intrinsic secondary structure. To understand this better, we compare AMPs with a ‘minimal’ mimic, a well characterized family of polydisperse cationic methacrylate-based random copolymer SMAMPs. Specifically, we focus on a comparison between the quantifiable membrane curvature generating capacity, charge density, and hydrophobicity of the polymeric SMAMPs and AMPs. Synchrotron small angle x-ray scattering (SAXS) results indicate that typical AMPs and these methacrylate SMAMPs generate similar amounts of membrane negative Gaussian curvature (NGC), which is topologically necessary for a variety of membrane-destabilizing processes. Moreover, the curvature generating ability of SMAMPs is more tolerant of changes in the lipid composition than that of natural AMPs with similar chemical groups, consistent with the lower specificity of SMAMPs. We find that, although the amount of NGC generated by these SMAMPs and AMPs are similar, the SMAMPs require significantly higher levels of hydrophobicity and cationic charge to achieve the same level of membrane deformation. We propose an explanation for these differences, which has implications for new synthetic strategies aimed at improved mimesis of AMPs.

Two interdependent mechanisms of antimicrobial activity allow for efficient killing in nylon-3-based polymeric mimics of innate immunity peptides

“…The preference for these nylon-3 polymers to generate cubic phases at a high PE content of 60–80% points to a mechanism of selectivity for bacterial membranes, such as that of E. coli , which has a composition of PG/PE/CL ≈ 20/70/10–20/75/5 [58,63]. We note that this mechanism is cognate with those observed for natural and synthetically derived AMPs [7,19,20,49,95]. …”

“…5). The five following compositions were used to model PE-rich prokaryotic membranes: DOPG/DOPE/CL = 10/80/10 and 20/60/20, DOPG/DOPE/DOPC = 20/80/0 and 20/60/20, and DOPS/DOPE = 20/80 [7,49,93]. The first three of these membranes served specifically to mimic that of E. coli , which is composed of PG/PE/CL ≈ 20/70–75/5–10 [58,63].…”

“…These AMP analogs have been demonstrated to provide various potential advantages over conventional antibiotics: (1) tunable, custom designs, (2) ease in preparation, (3) cost-effectiveness, (4) antibacterial potency with reduced likelihood of resistance, and (5) allowance for additional new built-in functions. In fact, recent work has highlighted quantitative differences between natural AMPs and their present synthetic analogs in terms of their hydrophobic content and cationic charge [49]. However, all unnatural AMP-mimetic oligomers have specific sequences of subunits, which require solid-phase synthesis, a technique that is costly and therefore not practical for many applications [6].…”

Direct Antimicrobial Activity of IFN-β

“…Earlier studies have identified a strong correlation between the formation of NGC and AMP-induced membrane destabilization mechanisms (11, 12, 34–37). NGC is also known as saddle-splay curvature, on which a surface curves upwards in one direction and downward in the perpendicular direction.…”

Controlling macromolecular structures towards effective antimicrobial polymers

“…Kuroda, Wong, L. Yang and co-workers conducted a mechanistic comparison between AMPs and synthetic mimics of antimicrobial peptides (SMAMPs), with regard to the cationic and hydrophobic content [40]. They found out that both systems can form similar amounts of negative Gaussian curvatures (NGCs).…”