Role of Structural Modifications in Peptidomimetic Compounds as Potential Antimicrobial Agents against Staphylococcus aureus and Streptococcus pyogenes: Balancing Bioavailability, Safety, and Antimicrobial Activity.
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Dzierżyńska M, Sawicka J, Łada K, Gajewicz-Skretna A, Deptuła M, Chernobrovkin A, Pogorzelska A, Grubb A, Zubarev RA, Pikuła M, Kasprzykowski F, Rodziewicz-Motowidło S
ACS Omega 10 (30) 33435-33460 [2025-08-05; online 2025-07-22]
The emergence of drug-resistant Gram-positive pathogens, particularlyStaphylococcus aureusandStreptococcus pyogenes, has driven the need for novel antimicrobial agents. This study explores 21 newly synthesized peptidomimetic analogues of cystatin C N-terminal fragment, designed to enhance bioactivity, solubility, and safety. These compounds were evaluated for antimicrobial potency, cytotoxicity, pro-proliferative effects, and pharmacokinetic properties. Key findings indicate that analogues A-192 and A-164 exhibited the strongest antimicrobial effects against S. aureus and S. pyogenes. Most compounds were inactive against Gram-negative bacteria. Cytotoxicity profiling identified several derivatives with low to moderate toxicity and favorable pro-proliferative effects at specific concentrations. Stability tests confirmed the robustness in aqueous and plasma environments. Computational absorption, distribution, metabolism, excretion, and toxicity (ADMET) modeling revealed low gastrointestinal absorption, but favorable parameters for topical applications. Exploratory analyses (principal component analysis (PCA) and two-way hierarchical cluster analysis (2D-HCA)) linked structural featuressuch as branching, molecular weight, and solubility, with biological activity. These results support the potential of structurally optimized peptidomimetics as targeted, topical therapeutics for Gram-positive infections and provide a rationale for further preclinical development.
PubMed 40787370
DOI 10.1021/acsomega.5c03775
Crossref 10.1021/acsomega.5c03775