2. Academic Validation
  3. Chalcogen-Varied Imidazolone Derivatives as Antibiotic Resistance Breakers in Staphylococcus aureus Strains

Chalcogen-Varied Imidazolone Derivatives as Antibiotic Resistance Breakers in Staphylococcus aureus Strains

  • Antibiotics (Basel). 2023 Nov 11;12(11):1618. doi: 10.3390/antibiotics12111618.
Karolina Witek 1 2 3 4,  Aneta Kaczor 1,  Ewa Żesławska 5,  Sabina Podlewska 1 6,  Małgorzata Anna Marć 1,  Kinga Czarnota-Łydka 1 7,  Wojciech Nitek 8,  Gniewomir Latacz 1,  Waldemar Tejchman 5,  Markus Bischoff 4,  Claus Jacob 3,  Jadwiga Handzlik 1
Affiliations

Affiliations

  • 1 Department of Technology and Biotechnology of Drugs, Jagiellonian University Medical College, Medyczna 9, 30-688 Krakow, Poland.
  • 2 Department of Pharmaceutical Microbiology, Jagiellonian University Medical College, Medyczna 9, 30-688 Krakow, Poland.
  • 3 Bioorganic Chemistry, School of Pharmacy, University of Saarland, Campus B2.1, D-66123 Saarbrüecken, Germany.
  • 4 Institute of Medical Microbiology and Hygiene, Saarland University, D-66421 Homburg, Germany.
  • 5 Institute of Biology and Earth Sciences, Pedagogical University of Krakow, Podchorążych 2, 30-084 Krakow, Poland.
  • 6 Maj Institute of Pharmacology, Polish Academy of Sciences, Smętna 12, 31-343 Krakow, Poland.
  • 7 Doctoral School of Medical and Health Sciences, Jagiellonian University Medical College, Św. Łazarza 15, 31-530 Krakow, Poland.
  • 8 Faculty of Chemistry, Jagiellonian University, Gronostajowa 2, 30-387 Krakow, Poland.
PMID: 37998820 DOI: 10.3390/antibiotics12111618
Abstract

In this study, a search for new therapeutic agents that may improve the Antibacterial activity of conventional Antibiotics and help to successfully overcome methicillin-resistant Staphylococcus aureus (MRSA) infections has been conducted. The purpose of this work was to extend the scope of our preliminary studies and to evaluate the Adjuvant potency of new derivatives in a set of S. aureus clinical isolates. The study confirmed the high efficacy of piperazine derivatives of 5-arylideneimidazol-4-one (7-9) tested previously, and it enabled the authors to identify even more efficient modulators of Bacterial resistance among new analogs. The greatest capacity to enhance oxacillin activity was determined for 1-benzhydrylpiperazine 5-spirofluorenehydantoin derivative (13) which, at concentrations as low as 0.0625 mM, restores the effectiveness of β-lactam Antibiotics against MRSA strains. In silico studies showed that the probable mechanism of action of 13 is related to the binding of the molecule with the allosteric site of PBP2a. Interestingly, thiazole derivatives tested were shown to act as both oxacillin and erythromycin conjugators in S. aureus isolates, suggesting a complex mode of action (i.e., influence on the Msr(A) efflux pump). This high enhancer activity indicates the high potential of imidazolones to become commercially available Antibiotic adjuvants.

Keywords

5-arylideneimidazoline-4-ones; MRSA; PBP2a; Staphylococcus aureus; antibiotic adjuvant; hydantoins; imidazolones; thiazole(s).

Figures
Products