Structure–activity relationship and crystallographic study of new monobactams

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

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.

• Jezik: Angleški jezik
• Ključne besede: antimicrobial agents, bacteria, inhibition, inhibitors, potassium
• 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: 2026
• Št. strani: Str. 3887-3901
• Številčenje: Vol. 69, iss. 4
• PID: 20.500.12556/RUL-180892
• UDK: 615.4:54
• ISSN pri članku: 1520-4804
• DOI: 10.1021/acs.jmedchem.5c02427
• COBISS.SI-ID: 271169027
• Datum objave v RUL: 19.03.2026

Gradivo je del revije

• Naslov: Journal of medicinal chemistry
• Skrajšan naslov: J. med. chem.
• Založnik: American Chemical Society
• ISSN: 1520-4804
• COBISS.SI-ID: 512806681

Licence

• Licenca: CC BY 4.0, Creative Commons Priznanje avtorstva 4.0 Mednarodna
• Povezava: http://creativecommons.org/licenses/by/4.0/deed.sl
• Opis: To je standardna licenca Creative Commons, ki daje uporabnikom največ možnosti za nadaljnjo uporabo dela, pri čemer morajo navesti avtorja.

Sekundarni jezik

• Jezik: Slovenski jezik
• Ključne besede: protimikrobna sredstva, bakterije, inhibitorji, zaviralci, derivati ​​monobaktama, farmacevtska kemija, kalij