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

Grabrijan, Katarina (avtor), Strašek Benedik, Nika (avtor), Krajnc, Alen (avtor), Bozovičar, Krištof (avtor), Knez, Damijan (avtor), Proj, Matic (avtor), Zdovc, Irena (avtor), Sosič, Izidor (avtor), Hrast, Martina (avtor), Gobec, Stanislav (avtor)

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.

• Jezik: Angleški jezik
• Ključne besede: antibacterial agents, monocyclic-β-lactams, penicillin-binding proteins, covalent inhibitors, transpeptidase
• Vrsta gradiva: Članek v reviji
• Tipologija: 1.01 - Izvirni znanstveni članek
• Organizacija: FFA - Fakulteta za farmacijo ; VF - Veterinarska fakulteta
• Status publikacije: Objavljeno
• Različica publikacije: Objavljena publikacija
• Leto izida: 2024
• Št. strani: Str. 423-440
• Številčenje: Vol. 74, no. 3
• PID: 20.500.12556/RUL-163495
• UDK: 615.4:54
• ISSN pri članku: 1846-9558
• DOI: 10.2478/acph-2024-0024
• COBISS.SI-ID: 206045187
• Datum objave v RUL: 08.10.2024

Gradivo je del revije

• Naslov: Acta pharmaceutica
• Skrajšan naslov: Acta pharm.
• Založnik: Croatian Pharmaceutical Society
• ISSN: 1846-9558
• COBISS.SI-ID: 3817585

Licence

• Licenca: CC BY-NC 4.0, Creative Commons Priznanje avtorstva-Nekomercialno 4.0 Mednarodna
• Povezava: http://creativecommons.org/licenses/by-nc/4.0/deed.sl
• Opis: Licenca Creative Commons, ki prepoveduje komercialno uporabo, vendar uporabniki ne rabijo upravljati materialnih avtorskih pravic na izpeljanih delih z enako licenco.

Sekundarni jezik

• Jezik: Slovenski jezik
• Ključne besede: antibakterijska sredstva, monociklični β-laktami, proteini, ki vežejo penicilin, kovalentni inhibitorji, transpeptidaza, farmacevtska kemija