Structure–activity relationship and crystallographic study of new monobactams

Kavaš, Vid (author), Contreras-Martel, Carlos (author), Pajk, Stane (author), Knez, Damijan (author), Martins, Alexandre (author), Gould, Thomas A. (author), Roper, David I. (author), Zdovc, Irena (author), Dessen, Andréa (author), Hrast Rambaher, Martina (author), Gobec, Stanislav (author)

Monobactams, a subclass of β-lactam antibiotics with a monocyclic scaffold, are uniquely resistant to hydrolysis by metallo-β-lactamases, providing a distinct therapeutic advantage. Here, we report an in silico-based structure–activity relationship (SAR) investigation of aztreonam-related monobactams. A focused library of monobactam derivatives was synthesized and evaluated for inhibition of penicillin-binding proteins (PBPs) and antibacterial activity. Ten compounds, including aztreonam, were crystallized with truncated PBP1b from Streptococcus pneumoniae, used as a model PBP. Potent PBP1b inhibitors were developed, although high enzymatic potency was not always reflected in strong antibacterial activity. Certain derivatives showed activity against Staphylococcus aureus, which is typically resistant to monobactams. 2D similarity search identified potent inhibitors active against Escherichia coli, Klebsiella pneumoniae, and Acinetobacter baumannii. Crystal structures revealed previously unrecognized binding interactions, including a halogen bond with a conserved threonine residue, underscoring the potential of these interactions to support the development of more potent PBP inhibitors.

• Language: English
• Keywords: antimicrobial agents, bacteria, inhibition, inhibitors, potassium
• 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: 2026
• Number of pages: Str. 3887-3901
• Numbering: Vol. 69, iss. 4
• PID: 20.500.12556/RUL-180892
• UDC: 615.4:54
• ISSN on article: 1520-4804
• DOI: 10.1021/acs.jmedchem.5c02427
• COBISS.SI-ID: 271169027
• Publication date in RUL: 19.03.2026

Record is a part of a journal

• Title: Journal of medicinal chemistry
• Shortened title: J. med. chem.
• Publisher: American Chemical Society
• ISSN: 1520-4804
• COBISS.SI-ID: 512806681

Licences

• License: CC BY 4.0, Creative Commons Attribution 4.0 International
• Link: http://creativecommons.org/licenses/by/4.0/
• Description: This is the standard Creative Commons license that gives others maximum freedom to do what they want with the work as long as they credit the author.

Secondary language

• Language: Slovenian
• Keywords: protimikrobna sredstva, bakterije, inhibitorji, zaviralci, derivati ​​monobaktama, farmacevtska kemija, kalij