Structure-function-guided exploration of the antimicrobial peptide polybia-CP identifies activity determinants and generates synthetic therapeutic candidates

Abstract

Antimicrobial peptides (AMPs) constitute promising alternatives to classical antibiotics for the treatment of drug-resistant infections, which are a rapidly emerging global health challenge. However, our understanding of the structure-function relationships of AMPs is limited, and we are just beginning to rationally engineer peptides in order to develop them as therapeutics. Here, we leverage a physicochemical-guided peptide design strategy to identify specific functional hotspots in the wasp-derived AMP polybia-CP and turn this toxic peptide into a viable antimicrobial. Helical fraction, hydrophobicity, and hydrophobic moment are identified as key structural and physicochemical determinants of antimicrobial activity, utilized in combination with rational engineering to generate synthetic AMPs with therapeutic activity in a mouse model. We demonstrate that, by tuning these physicochemical parameters, it is possible to design nontoxic synthetic peptides with enhanced sub-micromolar antimicrobial potency in vitro and anti-infective activity in vivo. We present a physicochemical-guided rational design strategy to generate peptide antibiotics.

Development and Challenges of Antimicrobial Peptides for Therapeutic Applications

“…Unlike receptor-binding peptides or peptide inhibitors that have specific binding targets, membrane-active peptides, whose activity is limited to specific cell membranes, are not well-defined. Their specificity is usually caused by their hydrophobic moment and electrostatic interactions, but exact mechanisms have not yet been determined [86][87][88]. These properties limit the ability to precisely tune the selectivity of membrane-active peptides toward a specific bacterial species [44,70,71,74,89,90].…”

“…These features optimize their pharmacokinetics and extend their elimination half-life so that they resist enzymatic degradation. The APD contains 3156 AMPs, 98% of which were discovered in nature [13]: many, in fact, were extracted from the skin secretions of frogs [44,[113][114][115] or are toxins from other species, e.g., bees, snakes, and wasps [86,116,117]. In contrast, all the FDA-approved AMPs were discovered in or derived from Gram-positive bacteria commonly found in the soil: Brevibacillus brevis (gramicidin), Streptomyces roseosporus (daptomycin), Amycolatopsis orientalis (vancomycin, which is the prototype of oritavancin, dalbavancin, and telavancin), and Paenibacillus polymyxa (colistin) [118].…”

“…Numerous approaches to peptide design have been introduced to make AMPs less toxic for humans while maintaining or improving their potency to eliminate bacteria [11,42], e.g., rational design [119,120], combinatorial peptide libraries [75,121], high-throughput screening [122,123], database-guided approaches [124,125], structure-function-guided design [86,126,127], and molecular dynamics simulations [44]. Three major methods to improve AMP function have been described: (i) High-throughput screening can be used to identify potential AMPs [128][129][130].…”

The wasp venom antimicrobial peptide polybia‐CP and its synthetic derivatives display antiplasmodial and anticancer properties

“…The role of peptides as antimicrobial agents has been extensively described in the literature. [1][2][3][4][5] New strategies for the design and development of these molecules, [6][7][8] combined with the rising resistance of microorganisms to standard antibiotics, 9,10 are boosting worldwide interest and studies on antimicrobial peptides (AMPs). For example, recent reports have described the design of AMPs with broadspectrum activity, particularly amphipathic cationic peptides.…”

“…29 The template and designed peptides were screened against P. sporozoites in the range of concentrations at which they presented antimicrobial activity against bacteria and fungi (0.39-6.25 μmol L −1 ). 6 Generally, naturally occurring small cationic peptides that are active against bacteria are not as active against Plasmodium. 13 In fact, Pol-CP-NH 2 did not exhibit antiplasmodial activity at the range of concentrations tested.…”