Structure–Activity Relationships of the Antimicrobial Peptide Natural Product Apidaecin

Abstract

With the growing crisis of antimicrobial resistance, it is critical to continue to seek out new sources of novel antibiotics. This need has led to renewed interest in natural product antimicrobials, specifically antimicrobial peptides. Nonlytic antimicrobial peptides are highly promising due to their unique mechanisms of action. One such peptide is apidaecin (Api), which inhibits translation termination through stabilization of the quaternary complex of the ribosome-apidaecin-tRNA-release factor. Synthetic derivatives of apidaecin have been developed, but structure-guided modifications have yet to be considered. In this work, we have focused on modifying key residues in the Api sequence that are responsible for the interactions that stabilize the quaternary complex. We present one of the first examples of a highly modified Api peptide that maintains its antimicrobial activity and interaction with the translation complex. These findings establish a starting point for further structure-guided optimization of Api peptides.

General Installation of (4H)-Imidazolone cis-Amide Bioisosteres Along the Peptide Backbone

“…We selected Apidaecin Ib (1–7, H-GNNRPVY-NH 2 ) as our model peptide to test imidazolone cyclization using the free −NH 2 group on the resin as our amine nucleophile. Apidaecin Ib and synthetic derivatives are currently being evaluated for their potential to treat multidrug-resistant Gram-negative pathogens. , Recently, Moore and co-workers showed that N-terminal guanidinylation of Apidaecin Ib peptide enhanced the antimicrobial activity and proteolytic stability . We hypothesized that imidazolones, a basic heterocyclic motif, might impart activity similar to that of the guanidinylated form by introducing a site for protonation.…”

Celebrating the 60th Anniversary of the MIKIW Meeting-in-Miniature: Virtual Special Issue

“…Researchers at MIKIW schools have been engaged in discovery of new anti-infective agents for many years, and this Virtual Special Issue contains three publications that focus on infectious diseases. These reports include medicinal chemistry work on apidaecin, a translation termination inhibitor and natural product derived from bees; new small-molecule inhibitors of the “brain-eating” amoeba, Naegleria fowleri ; and inhibitors of 4′-phospho­pante­theinyl transferase to treat Mycobacterium tuberculosis infections …”

Rationally Designed Novel Antimicrobial Peptides Targeting Chitin Synthase for Combating Soybean Phytophthora Blight

“…Unlike traditional antibiotics, which often target specific cellular processes and risk inducing resistance, the broad and nonspecific mode of action of AMPs makes it difficult for pathogens to develop resistance [ 17 ]. Additionally, some AMPs can penetrate cell membranes to target intracellular processes, further diversifying their mechanisms and reducing the likelihood of resistance [ 18 ]. Additionally, antimicrobial peptides exhibit broad-spectrum activity against various bacteria and have lower toxicity to host cells [ 19 , 20 ].…”