Skip to main content

Lund University Publications

LUND UNIVERSITY LIBRARIES

Role of Structural Modifications in Peptidomimetic Compounds as Potential Antimicrobial Agents against Staphylococcus aureus and Streptococcus pyogenes: Balancing Bioavailability, Safety, and Antimicrobial Activity

Dzierżyńska, Maria ; Sawicka, Justyna ; Łada, Katarzyna ; Gajewicz-Skretna, Agnieszka ; Deptuła, Milena ; Chernobrovkin, Alexey ; Pogorzelska, Aneta ; Grubb, Anders LU orcid ; Zubarev,, Roman and Pikuła, Michał , et al. (2025) In ACS Omega
Abstract
The emergence of drug-resistant Gram-positive pathogens, particularly
Staphylococcus aureusandStreptococcus pyogenes, has driven the need for novel antimicrobial agents. This study explores 21 newly synthesized peptidomimetic analogues of cystatin C Nterminal 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... (More)
The emergence of drug-resistant Gram-positive pathogens, particularly
Staphylococcus aureusandStreptococcus pyogenes, has driven the need for novel antimicrobial agents. This study explores 21 newly synthesized peptidomimetic analogues of cystatin C Nterminal 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 (2DHCA)) linked structural features such 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. (Less)
Please use this url to cite or link to this publication:
author
; ; ; ; ; ; ; ; and , et al. (More)
; ; ; ; ; ; ; ; ; ; and (Less)
organization
publishing date
type
Contribution to journal
publication status
published
subject
in
ACS Omega
publisher
The American Chemical Society (ACS)
ISSN
2470-1343
DOI
10.1021/acsomega.5c03775
language
English
LU publication?
yes
id
0fa08314-c780-4faa-aa00-17ee0280a837
date added to LUP
2025-07-24 10:56:47
date last changed
2025-07-24 16:01:16
@article{0fa08314-c780-4faa-aa00-17ee0280a837,
  abstract     = {{The emergence of drug-resistant Gram-positive pathogens, particularly<br/>Staphylococcus aureusandStreptococcus pyogenes, has driven the need for novel antimicrobial agents. This study explores 21 newly synthesized peptidomimetic analogues of cystatin C Nterminal 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.<br/>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 (2DHCA)) linked structural features such 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.}},
  author       = {{Dzierżyńska, Maria and Sawicka, Justyna and Łada, Katarzyna and Gajewicz-Skretna, Agnieszka and Deptuła, Milena and Chernobrovkin, Alexey and Pogorzelska, Aneta and Grubb, Anders and Zubarev,, Roman and Pikuła, Michał and Kasprzykowski, Franciszek and Rodziewicz-Motowidło, Sylwia}},
  issn         = {{2470-1343}},
  language     = {{eng}},
  month        = {{07}},
  publisher    = {{The American Chemical Society (ACS)}},
  series       = {{ACS Omega}},
  title        = {{Role of Structural Modifications in Peptidomimetic Compounds as Potential Antimicrobial Agents against Staphylococcus aureus and Streptococcus pyogenes: Balancing Bioavailability, Safety, and Antimicrobial Activity}},
  url          = {{http://dx.doi.org/10.1021/acsomega.5c03775}},
  doi          = {{10.1021/acsomega.5c03775}},
  year         = {{2025}},
}