Repurposing of compound libraries yields new inhibitors of NDM-1 metallo-β-lactamase with diverse zinc-binding moieties

Kavaš, Vid (avtor), Hinchliffe, Philip (avtor), Zorman, Maša (avtor), Krajnc, Alen (avtor), Proj, Matic (avtor), Golob, Majda (avtor), Hrast, Martina (avtor), Spencer, James (avtor), Gobec, Stanislav (avtor)

Antimicrobial resistance has emerged as a critical global public health threat, impacting human, animal and environmental health. An important mechanism of resistance is the production of β-lactamases, enzymes that hydrolyze the β-lactam ring, rendering β-lactam antibiotics ineffective. Metallo-β-lactamases (MBLs), which contain zinc ions in their active sites, are particularly challenging to counter as there are currently no inhibitors targeting these enzymes available on the market. Therefore, there is an urgent need for innovative drug discovery strategies to develop MBL-targeted therapies. New Delhi Metallo-β-Lactamase 1 (NDM-1) is the most widely disseminated MBL, with a global distribution in Enterobacterales. In this study, we used our library of fragment-sized chloroacetamides as a starting point to synthesize mercaptoacetamides as potential NDM-1 inhibitors. This resulted in a compound (14a) with an IC50 of 20 μM, which crystallography shows binds to NDM-1 in two different poses. Using this structure as a starting point for in silico design, we developed a series of larger thiol-based compounds designed to occupy more space in the active site and to utilize other novel zinc-binding groups. Although some showed minimal inhibition (which makes them valuable as decoys for metalloenzyme studies) one compound exhibited an IC50 of 14 μM, with crystallography indicating that an additional aromatic group, compared to 14a, interacts with hydrophobic residues on an NDM-1 active site loop. These data identify promising scaffolds for the further development of potent MBL inhibitors and show the utility of repurposing chemical libraries to target.clinically important enzymes.

• Jezik: Angleški jezik
• Ključne besede: mercaptoamides, New Delhi metallo-β-lactamase inhibitors, zinc-binding group library, in silico design
• 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: 2025
• Št. strani: 14 str.
• Številčenje: [article. no.] 100282, Vol. 15
• PID: 20.500.12556/RUL-171392
• UDK: 615.015.8
• ISSN pri članku: 2772-4174
• DOI: 10.1016/j.ejmcr.2025.100282
• COBISS.SI-ID: 241419779
• Datum objave v RUL: 25.08.2025

Gradivo je del revije

• Naslov: European journal of medicinal chemistry reports
• Založnik: Elsevier Masson SAS
• ISSN: 2772-4174
• COBISS.SI-ID: 96623107

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: merkaptoamidi, zaviralci metalo-β-laktamaz iz New Delhija, knjižnica skupin, ki vežejo cink, zasnova In silico, bakterijska rezistenca

Projekti

• Financer: ARIS - Javna agencija za znanstvenoraziskovalno in inovacijsko dejavnost Republike Slovenije
• Številka projekta: P1-0208
• Naslov: Farmacevtska kemija: načrtovanje, sinteza in vrednotenje učinkovin

• Financer: EC - European Commission
• Program financ.: H2020
• Številka projekta: 101021207
• Naslov: Predictive computational models for Enzyme Dynamics, Antimicrobial resistance, Catalysis and Thermoadaptation for Evolution and Design
• Akronim: PREDACTED