Peptidomimetics based on thiacalixarene with L-tyrosine moieties: Antibacterial activity against methicillin-resistant Staphylococcus aureus and degradation induced by binding to α-chymotrypsin

Abstract

The design of new antimicrobial agents is an important challenge due to the growing resistance of microorganisms to existing antibiotics. In recent years, the trend towards the development of compounds and materials with (bio)degradable properties has emerged. In this work, we propose and develop a method for the synthesis of new peptidomimetics, i.e., water-soluble macrocyclic quaternary ammonium salts containing L-tyrosine fragments based on p-tert-butylthiacalix[4]arene in various stereoisomeric forms (cone, partial cone, and 1,3-alternate). These compounds have low cytotoxicity (IC₅₀ = 80–267 μM) and high antibacterial activity (MIC = 0.5–15.6 μM) against Gram-positive bacterial strains including methicillin-resistant Staphylococcus aureus (MRSA). The obtained peptidomimetics can bind α-chymotrypsin with the formation of supramolecular systems and their subsequent degradation. Our results demonstrate the first example of multi-action thiacalixarene derivatives with antibacterial activity, protein binding ability and degradation induced by binding to α-chymotrypsin. The obtained results open the possibility of creating multi-action peptidomimetic systems with antimicrobial and biodegradable effect.