Izvorni znanstveni članak

https://doi.org/10.2478/acph-2024-0024

Synthesis and biochemical evaluation of new 3-amido-4-substituted monocyclic ß-lactams as inhibitors of penicillin-binding protein(s)

KATARINA GRABRIJAN ; The Department of Pharmaceutical Chemistry, Faculty of Pharmacy, University of Ljubljana, 1000 Ljubljana, Slovenia
NIKA STRAŠEK BENEDIK ; The Department of Pharmaceutical Chemistry, Faculty of Pharmacy, University of Ljubljana, 1000 Ljubljana, Slovenia
ALEN KRAJNC ; The Department of Pharmaceutical Chemistry, Faculty of Pharmacy, University of Ljubljana, 1000 Ljubljana, Slovenia
KRIŠTOF BOZOVIČAR ; The Department of Pharmaceutical Biology, Faculty of Pharmacy, University of Ljubljana, 1000 Ljubljana, Slovenia
DAMIJAN KNEZ ; The Department of Pharmaceutical Chemistry, Faculty of Pharmacy, University of Ljubljana, 1000 Ljubljana, Slovenia
MATIC PROJ ; The Department of Pharmaceutical Chemistry, Faculty of Pharmacy, University of Ljubljana, 1000 Ljubljana, Slovenia
IRENA ZDOVC ; Institu te of Microbiology and Parasitology, Veterinary Faculty, University of Ljubljana, 1000 Ljubljana, Slovenia
IZIDOR SOSIČ ; The Department of Pharmaceutical Chemistry, Faculty of Pharmacy, University of Ljubljana, 1000 Ljubljana, Slovenia
CARLOS CONTRERAS-MARTEL ; University Grenoble Alpes, CNRS, CEA, Institut de Biologie Structurale (IBS), Bacterial Pathogenesis Group, F-38044 Grenoble, France
ANDRÉA DESSEN ; University Grenoble Alpes, CNRS, CEA, Institut de Biologie Structurale (IBS), Bacterial Pathogenesis Group, F-38044 Grenoble, France
MARTINA HRAST RAMBAHER ; The Department of Pharmaceutical Chemistry, Faculty of Pharmacy, University of Ljubljana, 1000 Ljubljana, Slovenia
STANISLAV GOBEC ; The Department of Pharmaceutical Chemistry, Faculty of Pharmacy, University of Ljubljana, 1000 Ljubljana, Slovenia *

* Autor za dopisivanje.

Sažetak

In the final phases of bacterial cell wall synthesis, penicillin-binding proteins (PBPs) catalyze the cross-linking of peptidoglycan. For many decades, effective and non-toxic β-lactam antibiotics have been successfully used as mimetics of the D-Ala-D-Ala moiety of the natural substrate and employed as irreversible inhibitors of PBPs. In the years following their discovery, the emergence of resistant bacteria led to a decline in their clinical efficacy. Using Staudinger cycloaddition, we synthesized a focused library of novel monocyclic β-lactams in which different substituents were introduced at the C4 position of the β-lactam ring, at the C3 amino position, and at the N1 lactam nitrogen. In biochemical assays, the compounds were evaluated for their inhibitory effect on the model enzyme PBP1b from Streptococcus pneumoniae. Upon investigation of the antibacterial activity of the newly prepared compounds against ESKAPE pathogens, some compounds showed moderate inhibition. We also examined their reactivity and selectivity in a biochemical assay with other enzymes that have a catalytic serine in the active site, such as human cholinesterases, where they also showed no inhibitory activity, highlighting their specificity for bacterial targets. These compounds form the basis for further work on new monocyclic β-lactams with improved antibacterial activity.

Ključne riječi

antibacterial agents; monocyclic-β-lactams; penicillin-binding proteins; covalent inhibitors; transpeptidase

Hrčak ID:

317612

URI

https://hrcak.srce.hr/317612

Datum izdavanja:

30.9.2024.

Posjeta: 0 *