Antimicrobial Peptide Mimics for Clinical Use: Does Size Matter?

Abstract

The search for efficient antimicrobial therapies that can alleviate suffering caused by infections from resistant bacteria is more urgent than ever before. Infections caused by multi-resistant pathogens represent a significant and increasing burden to healthcare and society and researcher are investigating new classes of bioactive compounds to slow down this development. Antimicrobial peptides from the innate immune system represent one promising class that offers a potential solution to the antibiotic resistance problem due to their mode of action on the microbial membranes. However, challenges associated with pharmacokinetics, bioavailability and off-target toxicity are slowing down the advancement and use of innate defensive peptides. Improving the therapeutic properties of these peptides is a strategy for reducing the clinical limitations and synthetic mimics of antimicrobial peptides are emerging as a promising class of molecules for a variety of antimicrobial applications. These compounds can be made significantly shorter while maintaining, or even improving antimicrobial properties, and several downsized synthetic mimics are now in clinical development for a range of infectious diseases. A variety of strategies can be employed to prepare these small compounds and this review describes the different compounds developed to date by adhering to a minimum pharmacophore based on an amphiphilic balance between cationic charge and hydrophobicity. These compounds can be made as small as dipeptides, circumventing the need for large compounds with elaborate three-dimensional structures to generate simplified and potent antimicrobial mimics for a range of medical applications. This review highlight key and recent development in the field of small antimicrobial peptide mimics as a promising class of antimicrobials, illustrating just how small you can go.

Effect of regio- and stereoisomerism on antifouling 2,5-diketopiperazines

“…32 For short linear peptides which obey this pharmacophore, changes to peptide sequence (order of residues) and stereochemistry can increase activity against both MRSA and some marine fouling organisms. 34,36,38,39 In addition, a close correlation between solution amphiphilicity and bioactivity has been reported for compounds of this type. 36,37 Within the natural antifouling halogenated dipeptide scaffold, structural contributions other than the 2 + 2 pharmacophore are in operation, as exemplified by the high potency of several disubstituted natural cationic antifoulants such as (1) 20 and the synoxazolidinones 23,40 and their analogs.…”

“…34,36,38,39 In addition, a close correlation between solution amphiphilicity and bioactivity has been reported for compounds of this type. 36,37 Within the natural antifouling halogenated dipeptide scaffold, structural contributions other than the 2 + 2 pharmacophore are in operation, as exemplified by the high potency of several disubstituted natural cationic antifoulants such as (1) 20 and the synoxazolidinones 23,40 and their analogs. These marine compounds are active antifoulants but they have poor antibacterial activity against terrestrial bacteria.…”

“…Organic & Biomolecular Chemistry against marine organisms as it is against terrestrial microorganisms. 36 Within the regioisomeric series 6-8, 6 and 8 demonstrated broad-spectrum antifouling activity comparable to that of lead 2. These compounds had low to sub-µg mL −1 LC 50 -values against the four macrofouling organisms, the most susceptible being S. cariniferus (Table 1).…”

“…33,42 The natural three methylene unit sidechain of Arg was chosen as the cationic guanidine functionality over alternative basic groups because of reported improvements in activity and reduced toxicity. 32,36,43 DKPs 3-5 were prepared to probe the 2 + 2 pharmacophore in the marine setting by systematically adding groups to the DKP scaffold to alter the charge/hydrophobicity balance, whereas 6-8 were intended to investigate the substitution pattern around the DKP core by switching the groups at the C α /N α positions compared to lead 2. Compounds 9 and 10 were included to investigate the stereochemical impact on marine antifouling activity.…”

“…33,34 This pharmacophore stipulates that the minimum requirement for potent antimicrobial activity is two units of hydrophobic bulk and two units of cationic charge, often referred to as the "2 + 2 pharmacophore". 33,35,36 It has been shown that these compounds target the plasma membrane of bacteria, causing membrane disruption ultimately leading to cell death, and the broad-spectrum nature of these compounds provides a promising platform for further optimisation of effective marine antifouling biocides. 34,37 Symmetric enantiopure DKPs adhering to the 2 + 2 pharmacophore have been confirmed to display broad-spectrum antifouling activity matching that reported for the linear peptide analogs.…”