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.
Highlights
Antimicrobial peptides (AMPs) constitute promising alternatives to classical antibiotics for the treatment of drug-resistant infections, which are a rapidly emerging global health challenge
The chemically synthesized wild-type peptide was active against E. coli [minimal inhibitory concentration (MIC) = 8.0 μmol L−1] and presented the same activity against S. aureus and both of the P. aeruginosa strains tested (MIC = 64.0 μmol L−1 — Fig. 2a)
We describe a systematic structure–activity relationship design approach aimed at revealing the sequence requirements for antimicrobial activity of a natural wasp venom AMP30 and several of its derivatives
Summary
Antimicrobial peptides (AMPs) constitute promising alternatives to classical antibiotics for the treatment of drug-resistant infections, which are a rapidly emerging global health challenge. Despite of some obstacles, such as short serum half-life of small linear natural peptides and intrinsic bacterial resistance (i.e., membrane modifications, efflux pump and proteolytic degradation) to certain host defense peptides[8], AMPs are a promising alternative to conventional antibiotics because of their unique diversity of peptide sequences. Their sequence space is almost unlimited, and a wide range of amino acids is available in nature[9]. Some AMPs antimicrobial mode of action include targeting key cellular processes and metabolic pathways[21,22] including DNA and protein synthesis[23,24], protein folding, enzymatic activity and cell wall synthesis[25], cell division[26], RNA synthesis[27], inactivation of chaperone proteins necessary for proper folding, and even targeting mitochondria[28]
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