ABSTRACT
Translocase MraY is the target for bacteriophage ÏX174 lysis protein E, which interacts via a protein-protein interaction mediated by Phe-288 and Glu-287 of E. coli MraY, and an Arg-Trp-x-x-Trp motif on protein E, also found in several cationic antimicrobial peptides. Analogues of Arg-Trp-octyl ester, found previously to show antimicrobial activity, were tested for antimicrobial activity, with Lys-Trp-oct (MIC50P. fluorescens 5 µg/mL) and Arg-Trp-decyl ester (MIC50P. fluorescens 3 µg/mL) showing enhanced antimicrobial activity. Synthesis and testing of α-helix peptidomimetic analogues for this motif revealed improved antibacterial activity (MIC50E. coli 4-7 µg/mL) for analogues containing two aromatic substituents, mimicking the Arg-Trp-x-x-Trp motif, and MraY inhibition (IC50 140 µM) by one such peptidomimetic. Investigation of mechanism of action using the Alamar Blue membrane permeabilisation assay revealed bacteriostatic and bacteriocidal mechanisms in different members of this set of compounds, raising the possibility of more than one biological target. The observed antimicrobial activity and MraY inhibition shown by peptidomimetic compounds confirms that this site could be targeted by drug-like molecules.
Subject(s)
Anti-Bacterial Agents/pharmacology , Antimicrobial Peptides/pharmacology , Bacterial Proteins/antagonists & inhibitors , Peptidomimetics/pharmacology , Transferases (Other Substituted Phosphate Groups)/antagonists & inhibitors , Viral Proteins/antagonists & inhibitors , Anti-Bacterial Agents/chemical synthesis , Anti-Bacterial Agents/chemistry , Antimicrobial Peptides/chemical synthesis , Antimicrobial Peptides/chemistry , Bacterial Proteins/metabolism , Dose-Response Relationship, Drug , Escherichia coli/drug effects , Microbial Sensitivity Tests , Molecular Structure , Peptidomimetics/chemical synthesis , Peptidomimetics/chemistry , Pseudomonas aeruginosa/drug effects , Structure-Activity Relationship , Transferases (Other Substituted Phosphate Groups)/metabolism , Viral Proteins/metabolismABSTRACT
In response to the dual challenges of increasingly risky target portfolios and realignment of traditional pharmaceutical company resources away from early-phase research and development (R&D), research groups have sought to engage across the industrial and not-for-profit divide, resulting in the emergence of many different collaborative models. Here, we describe two successful collaborations based upon shared commitment and risk. The risks and complexities of external collaboration can be mitigated by appropriate agreements and tools, but we found that it remains essential that the collaborating scientists adopt a collaborative mindset and embrace the diverse ways of working of partner organizations.
Subject(s)
Biomedical Research/organization & administration , Cooperative Behavior , Drug Discovery , Chemistry, Pharmaceutical , Drug Industry , Risk , UniversitiesABSTRACT
A direct synthetic approach to the spiro-γ-lactone clerodane ring system has been investigated. This work builds on that of Jung and highlights the inherent difficulties associated with the otherwise obvious Diels-Alder approach.
Subject(s)
Diterpenes, Clerodane/chemistry , Models, Molecular , Molecular Structure , Spiro Compounds/chemistryABSTRACT
A cleavable linker strategy has been used to optimise the enolate alkylation reactions of a recyclable L-tyrosine derived polymer-supported oxazolidin-2-one for the asymmetric synthesis of a series of chiral alpha-alkyl acids.