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

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

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.

• Language: English
• Keywords: antibacterial agents, monocyclic-β-lactams, penicillin-binding proteins, covalent inhibitors, transpeptidase
• Work type: Article
• Typology: 1.01 - Original Scientific Article
• Organization: FFA - Faculty of Pharmacy; VF - Veterinary Faculty
• Publication status: Published
• Publication version: Version of Record
• Year: 2024
• Number of pages: Str. 423-440
• Numbering: Vol. 74, no. 3
• PID: 20.500.12556/RUL-163495
• UDC: 615.4:54
• ISSN on article: 1846-9558
• DOI: 10.2478/acph-2024-0024
• COBISS.SI-ID: 206045187
• Publication date in RUL: 08.10.2024

Record is a part of a journal

• Title: Acta pharmaceutica
• Shortened title: Acta pharm.
• Publisher: Croatian Pharmaceutical Society
• ISSN: 1846-9558
• COBISS.SI-ID: 3817585

Licences

• License: CC BY-NC 4.0, Creative Commons Attribution-NonCommercial 4.0 International
• Link: http://creativecommons.org/licenses/by-nc/4.0/
• Description: A creative commons license that bans commercial use, but the users don’t have to license their derivative works on the same terms.

Secondary language

• Language: Slovenian
• Keywords: antibakterijska sredstva, monociklični β-laktami, proteini, ki vežejo penicilin, kovalentni inhibitorji, transpeptidaza, farmacevtska kemija