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Improving Activity of New Arylurea Agents against Multidrug-Resistant and Biofilm-Producing Staphylococcus
Vittorio Canale1, Iwona Skiba-Kurek1, Karolina Klesiewicz1
1Faculty of Pharmacy Jagiellonian University Medical College, 9 Medyczna Str., 30-688 Kraków, Poland.
Abstract:
Multidrug-resistant (MDR) strains of Staphylococcus epidermidis (S. epidermidis), prevalent in hospital environments, contribute to increased morbidity and mortality, especially among newborns, posing a critical concern for neonatal sepsis. In response to the pressing demand for novel antibacterial therapies, we present findings from synthetic chemistry and structure-activity relationship studies focused on arylsulfonamide/arylurea derivatives of aryloxy[1-(thien-2-yl)propyl]piperidines. Through bioisosteric replacement of the sulfonamide fragment with a urea moiety, compound 25 was identified, demonstrating potent bacteriostatic activity against clinical multidrug-resistant S. epidermidis strains (MIC50 and MIC90 = 1.6 and 3.125 μg/mL). Importantly, it showed activity against linezolid-resistant strains and exhibited selectivity over mammalian cells. Compound 25 displayed antibiofilm-forming properties against clinical S. epidermidis strains and demonstrated the capacity to eliminate existing biofilm layers. Additionally, it induced complete depolarization of the bacterial membrane in clinical S. epidermidis strains. In light of these findings, targeting bacterial cell membranes with compound 25 emerges as a promising strategy in the fight against multidrug-resistant S. epidermidis strains.
Insights
A new compound, 25, shows potent activity against multidrug-resistant Staphylococcus epidermidis, including linezolid-resistant strains. This compound targets bacterial cell membranes and prevents biofilm formation, offering a promising new therapy for neonatal sepsis.
Area of Science:
- Medicinal Chemistry
- Microbiology
- Drug Discovery
Background:
- Multidrug-resistant Staphylococcus epidermidis (MDR S. epidermidis) is a significant threat in healthcare settings, particularly for neonatal sepsis.
- Existing treatments face challenges due to emerging resistance, necessitating the development of novel antibacterial agents.
Purpose of the Study:
- To identify novel antibacterial compounds targeting MDR S. epidermidis.
- To explore structure-activity relationships of arylsulfonamide/arylurea derivatives.
Main Methods:
- Synthetic chemistry and structure-activity relationship studies were conducted.
- Compound 25 was synthesized and evaluated for its activity against clinical MDR S. epidermidis strains.
- Antibiofilm activity and membrane depolarization effects were assessed.
Main Results:
- Compound 25 demonstrated potent bacteriostatic activity against MDR S. epidermidis (MIC50 and MIC90 = 1.6 and 3.125 μg/mL).
- It was effective against linezolid-resistant strains and selective for bacterial over mammalian cells.
- Compound 25 inhibited biofilm formation, eradicated existing biofilms, and depolarized bacterial membranes.
Conclusions:
- Compound 25 represents a promising lead compound for combating MDR S. epidermidis infections.
- Targeting bacterial cell membranes is a viable strategy against these resistant pathogens.
- Further development of compound 25 could lead to effective therapies for neonatal sepsis.
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