Short Tryptamine-Based Peptoids as Potential Therapeutics for Microbial Keratitis: Structure-Function Correlation Studies

Abstract

Peptoids are peptidomimetics that have attracted considerable interest as a promising class of antimicrobials against multi-drug-resistant bacteria due to their resistance to proteolysis, bioavailability, and thermal stability compared to their corresponding peptides. Staphylococcus aureus is a significant contributor to infections worldwide and is a major pathogen in ocular infections (keratitis). S. aureus infections can be challenging to control and treat due to the development of multiple antibiotic resistance. This work describes short cationic peptoids with activity against S. aureus strains from keratitis. The peptoids were synthesized via acid amine-coupling between naphthyl-indole amine or naphthyl-phenyl amine with different amino acids to produce primary amines (series I), mono-guanidines (series II), tertiary amine salts (series III), quaternary ammonium salts (series IV), and di-guanidine (series V) peptoids. The antimicrobial activity of the peptoids was compared with ciprofloxacin, an antibiotic that is commonly used to treat keratitis. All new compounds were active against Staphylococcus aureus S.aureus 38. The most active compounds against S.aur38 were 20a and 22 with MIC = 3.9 μg mL−1 and 5.5 μg mL−1, respectively. The potency of these two active molecules was investigated against 12 S. aureus strains that were isolated from microbial keratitis. Compounds 20a and 22 were active against 12 strains with MIC = 3.2 μg mL−1 and 2.1 μg mL−1, respectively. There were two strains that were resistant to ciprofloxacin (Sa.111 and Sa.112) with MIC = 128 μg mL−1 and 256 μg mL−1, respectively. Compounds 12c and 13c were the most active against E. coli, with MIC > 12 μg mL−1. Cytoplasmic membrane permeability studies suggested that depolarization and disruption of the bacterial cell membrane could be a possible mechanism for antibacterial activity and the hemolysis studies toward horse red blood cells showed that the potent compounds are non-toxic at up to 50 μg mL−1.

Biofilms and contact lenses: problems and solutions

“…30 However, we did show that the lenses slowly lost activity during wear most probably due to proteolysis, 31 which may have been the reason they did not show any greater reduction in incidence of inflammation. We have now developed antimicrobial cationic peptide mimics [32][33][34] and tested peptoids, 35 which are proteolytically stable and some of which we have recently shown to be able to reduce microbial colonisation, to a greater degree than our cationic peptide, when bound to contact lenses. We are now setting up to test these in preclinical tests before embarking on clinical trials.…”

The activity of antimicrobial peptoids against multidrug-resistant ocular pathogens

“…They can be more potent than AMPs [ 31 ]. For example, peptoids can have minimum inhibitory concentrations as low as 1.8 μg mL −1 against Bacillus subtilis and 12.4 μg mL −1 against Escherichia coli , whereas these bacteria had MICs of 4.5 μg mL −1 and 35.6 μg mL −1 , respectively, with the AMP melittin [ 31 ] Di-guanidine peptoids, produced via acid amine-coupling between naphthyl-indole amine and with different amino acids were more potent against S. aureus , giving MICs of 2.1–6.4 μg mL −1 compared to the MIC of ciprofloxacin which ranged from 8 to 256 μg mL −1 [ 38 ]. Furthermore, peptoids can be active against all the ESKAPE pathogens [ 39 ], which are the primary cause of nosocomial (hospital-acquired) infections, as well as bacterial persister cells [ 40 ], viruses [ 41 ], fungi [ 40 ], and parasites [ 42 ].…”