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针对产金属β-内酰胺酶细菌的1,4,7-三氮杂环壬烷偶联β-内酰胺的研发与评估

Development and evaluation of 1,4,7-triazacyclononane-coupled β-lactams against metallo-β-lactamase producing bacteria.

作者信息

Shungube Mbongeni, Reddy Nakita, Ghazi Terisha, Govender Kimberleigh B, Singh Ravesh, Kajee Afsana, Chuturgoon Anil, Kruger Hendrik G, Arvidsson Per I, Tiwari Dileep, Govender Thavendran, Naicker Tricia

机构信息

Catalysis and Peptide Research Unit, University of KwaZulu-Natal Durban 4001 South Africa

Office of AIDS and TB, South African Medical Research Council 1 Soutpansberg Road Pretoria South Africa.

出版信息

RSC Adv. 2025 Jul 7;15(29):23427-23440. doi: 10.1039/d5ra01842k. eCollection 2025 Jul 4.

DOI:10.1039/d5ra01842k
PMID:40626067
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC12230942/
Abstract

Antimicrobial resistance (AMR) is a critical global issue, particularly against β-lactam antibiotics, which comprise over 60% of prescriptions. Metallo-β-lactamases (MBLs) are especially concerning as they inactivate nearly all β-lactams, except monobactams. Unlike serine-β-lactamases (SBLs), for which inhibitors exist, there are no clinically approved MBL inhibitors; only taniborbactam is in pre-registration. This study introduces eight new MBL inhibitors (13a-f, 14a-b), designed using a 1,4,7-triazacyclononane (NO3PY) chelator linked to a β-lactam. These inhibitors restored the efficacy of meropenem, reducing its minimum inhibitory concentration (MIC) against MBL-expressing pathogens to <2 mg L. Time-kill assays confirmed bactericidal activity, with this series being non-toxic and highly specific, these compounds hold promising potential as MBL inhibitors.

摘要

抗菌药物耐药性（AMR）是一个严峻的全球性问题，尤其是针对β-内酰胺类抗生素，此类抗生素占处方量的60%以上。金属β-内酰胺酶（MBL）尤其令人担忧，因为它们能使几乎所有β-内酰胺类抗生素失活，单环β-内酰胺类抗生素除外。与存在抑制剂的丝氨酸β-内酰胺酶（SBL）不同，目前尚无临床批准的MBL抑制剂；只有替尼硼巴坦处于注册前阶段。本研究介绍了八种新型MBL抑制剂（13a - f，14a - b），它们是通过将1,4,7 - 三氮杂环壬烷（NO3PY）螯合剂与β-内酰胺相连设计而成。这些抑制剂恢复了美罗培南的疗效，将其对表达MBL的病原体的最低抑菌浓度（MIC）降低至<2 mg/L。时间杀菌试验证实了其杀菌活性，该系列无毒且具有高度特异性，这些化合物作为MBL抑制剂具有广阔的应用前景。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/254f/12230942/4fee6aca2494/d5ra01842k-f4.jpg
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https://cdn.ncbi.nlm.nih.gov/pmc/blobs/254f/12230942/8e539c83b71b/d5ra01842k-f3.jpg
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https://cdn.ncbi.nlm.nih.gov/pmc/blobs/254f/12230942/32d39c1e7db3/d5ra01842k-f1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/254f/12230942/340ec7ed2a52/d5ra01842k-s1.jpg
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Neutralizing Carbapenem Resistance by Co-Administering Meropenem with Novel β-Lactam-Metallo-β-Lactamase Inhibitors.美罗培南与新型β-内酰胺-金属β-内酰胺酶抑制剂联合使用以中和碳青霉烯类耐药性
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