A study on antimicrobial activity of lysine-like peptoids for the development of new antimicrobials

Abstract

The development of new medicines with unique methods of antimicrobial action is desperately needed due to the emerging multidrug-resistant bacteria, such as methicillin-resistant Staphylococcus aureus. Therefore, antimicrobial peptoids have emerged as potential new antimicrobials. Thirteen peptoid analogues have been designed and synthesized via solid phase synthesis. These peptoids have undergone a biological analysis to determine the structure-activity relationships that define their antibacterial activity. Each peptoid is composed of nine repeating N-substituted glycine monomers (9-mer). The monomer units were synthesized with three distinct alkyl side chain lengths: four-carbon butyl monomers, six-carbon hexyl monomers, and eight-carbon octyl monomers. Out of 12 different peptoids, only one peptoid called Tosyl-Octyl-Peptoid (TOP) demonstrated significant broad-spectrum bactericidal activity. TOP kills bacteria under non-dividing and dividing conditions. The Minimum Inhibitory Concentrations values of TOP for Staphylococcus epidermidis, Escherichia coli and Klebsiella were 20 µM, whereas Methicillin-resistant Staphylococcus aureus and Methicillin-sensitive Staphylococcus aureus were 40 µM. The highest MIC values were observed for Pseudomonas aeruginosa at 80 µM. The selectivity ratio was calculated, by dividing the 10% haemolysis activity (5 mM) by the median of the MIC (50 µM) yielding a selective ratio for TOP as 100. This selective ratio is well above previously reported peptidomimetics selective ratio of around 20. TOP shows broad-spectrum bactericidal action in both dividing and non-dividing bacteria in co-culture systems and intracellular bacterial killing activity. These results add new information about the antimicrobial peptoids and aid in the future design of synthetic peptoids with increased therapeutic potential.