(Re)Defining the Proline-Rich Antimicrobial Peptide Family and the Identification of Putative New Members.

Nicholas G Welch,John D Wade,Mohammed Akhter Hossain,Wenyi Li,Neil M O'Brien-Simpson,Frances Separovic

doi:10.3389/fchem.2020.607769

Abstract

As we rapidly approach a post-antibiotic era in which multi-drug resistant bacteria are ever-pervasive, antimicrobial peptides (AMPs) represent a promising class of compounds to help address this global issue. AMPs are best-known for their membrane-disruptive mode of action leading to bacteria cell lysis and death. However, many AMPs are also known to be non-lytic and have intracellular modes of action. Proline-rich AMPs (PrAMPs) are one such class, that are generally membrane permeable and inhibit protein synthesis leading to a bactericidal outcome. PrAMPs are highly effective against Gram-negative bacteria and yet show very low toxicity against eukaryotic cells. Here, we review both the PrAMP family and the past and current definitions for this class of peptides. Computational analysis of known AMPs within the DRAMP database (http://dramp.cpu-bioinfor.org/) and assessment of their PrAMP-like properties have led us to develop a revised definition of the PrAMP class. As a result, we subsequently identified a number of unknown and unclassified peptides containing motifs of striking similarity to known PrAMP-based DnaK inhibitors and propose a series of new sequences for experimental evaluation and subsequent addition to the PrAMP family.

Highlights

Antimicrobial peptides (AMPs) are a well-known class of naturally occurring compounds with potent bactericidal activity
Proline-rich AMPs (PrAMPs) are a fascinating class of membrane permeable peptides with intracellular targets of DnaK or the 70S ribosome
Based on a rigorous analysis of known PrAMPs from the literature, we propose a new set of definitions to describe members of the PrAMP family

Summary

INTRODUCTION

Antimicrobial peptides (AMPs) are a well-known class of naturally occurring compounds with potent bactericidal activity. There is nothing remarkable about the newly identified sequences: they have proline content range of 25–38%; a length range of 19–34; and a net charge range of +2 to +7, but they may qualify for membership within the PrAMP family given their feature similarity to known PrAMPs. we sought to evaluate the likelihood of other PRPcontaining AMPs as PrAMPs. From the obtained 75 “PrAMPlike” sequences in DRAMP database, we identified 34 sequences containing the PRP motif. While its intracellular target and mode of action have yet to be identified, (Rabel et al, 2004), given the similarity to known PrAMPs and its synergistic activity, attacin-C may be a DnaK inhibitor despite not appearing to be membrane permeable At this point, without confirmed antimicrobial activity, attacin-C may be best considered as an AMP adjuvant (Sheard et al, 2019). PRbombesin is likely a DnaK binder and would be a member of the PrAMP family

CONCLUSIONS

METHODS

Findings

DATA AVAILABILITY STATEMENT