Cefepime-taniborbactam and ceftibuten-ledaborbactam maintain activity against KPC variants that lead to ceftazidime-avibactam resistance.

IF 4.1 2区 医学 Q2 MICROBIOLOGY
Antimicrobial Agents and Chemotherapy Pub Date : 2025-03-05 Epub Date: 2025-02-10 DOI:10.1128/aac.01511-24
Cullen L Myers, Annie Stevenson, Brittany Miller, Denis M Daigle, Tsuyoshi Uehara, Daniel C Pevear
{"title":"Cefepime-taniborbactam and ceftibuten-ledaborbactam maintain activity against KPC variants that lead to ceftazidime-avibactam resistance.","authors":"Cullen L Myers, Annie Stevenson, Brittany Miller, Denis M Daigle, Tsuyoshi Uehara, Daniel C Pevear","doi":"10.1128/aac.01511-24","DOIUrl":null,"url":null,"abstract":"<p><p><i>Klebsiella pneumoniae</i> carbapenemases (KPCs) are widespread β-lactamases that are a major cause of clinical non-susceptibility of Gram-negative bacteria to carbapenems and other β-lactam antibiotics. Ceftazidime combined with the β-lactamase inhibitor avibactam (CAZ-AVI) has been effective in treating infections by KPC-producing bacteria, but emerging KPC variants confer resistance to the combination. Taniborbactam and ledaborbactam are bicyclic boronate β-lactamase inhibitors currently under development with cefepime and ceftibuten, respectively, to treat carbapenem-resistant bacterial infections. Here, we assessed the effects of clinically important KPC-2 and KPC-3 variants (V240G, D179Y, and D179Y/T243M) on the antibacterial activity of cefepime-taniborbactam (FEP-TAN) and ceftibuten-ledaborbactam (CTB-LED) and examined catalytic activity and inhibition of these variants. Unlike CAZ-AVI, FEP-TAN and CTB-LED were highly active against <i>Escherichia coli</i> strains expressing these KPC variants. Experiments with purified enzymes showed that FEP and CTB were poorly hydrolyzed by the KPC variants and had weak affinity for variants containing D179Y. In addition, the D179Y substitution in KPC-2 reduced inhibition by TAN and LED, but inactivation efficiencies (<i>k</i><sub>2</sub>/<i>K</i>) for these inhibitors were significantly higher than those for AVI. <i>K</i><sub>2</sub>/<i>K</i> was less affected for D179Y-containing KPC-3 variants, and robust inhibition was observed by TAN, LED, and AVI. Together, the findings illustrate a biochemical basis for FEP-TAN and CTB-LED efficacy in KPC variant-mediated CAZ-AVI resistance backgrounds, whereby the boronate inhibitors have sufficient inhibitory activity, while FEP and CTB are poor substrates and bind to the variant enzymes with reduced affinity.</p>","PeriodicalId":8152,"journal":{"name":"Antimicrobial Agents and Chemotherapy","volume":" ","pages":"e0151124"},"PeriodicalIF":4.1000,"publicationDate":"2025-03-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11881561/pdf/","citationCount":"0","resultStr":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"Antimicrobial Agents and Chemotherapy","FirstCategoryId":"3","ListUrlMain":"https://doi.org/10.1128/aac.01511-24","RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"2025/2/10 0:00:00","PubModel":"Epub","JCR":"Q2","JCRName":"MICROBIOLOGY","Score":null,"Total":0}
引用次数: 0

Abstract

Klebsiella pneumoniae carbapenemases (KPCs) are widespread β-lactamases that are a major cause of clinical non-susceptibility of Gram-negative bacteria to carbapenems and other β-lactam antibiotics. Ceftazidime combined with the β-lactamase inhibitor avibactam (CAZ-AVI) has been effective in treating infections by KPC-producing bacteria, but emerging KPC variants confer resistance to the combination. Taniborbactam and ledaborbactam are bicyclic boronate β-lactamase inhibitors currently under development with cefepime and ceftibuten, respectively, to treat carbapenem-resistant bacterial infections. Here, we assessed the effects of clinically important KPC-2 and KPC-3 variants (V240G, D179Y, and D179Y/T243M) on the antibacterial activity of cefepime-taniborbactam (FEP-TAN) and ceftibuten-ledaborbactam (CTB-LED) and examined catalytic activity and inhibition of these variants. Unlike CAZ-AVI, FEP-TAN and CTB-LED were highly active against Escherichia coli strains expressing these KPC variants. Experiments with purified enzymes showed that FEP and CTB were poorly hydrolyzed by the KPC variants and had weak affinity for variants containing D179Y. In addition, the D179Y substitution in KPC-2 reduced inhibition by TAN and LED, but inactivation efficiencies (k2/K) for these inhibitors were significantly higher than those for AVI. K2/K was less affected for D179Y-containing KPC-3 variants, and robust inhibition was observed by TAN, LED, and AVI. Together, the findings illustrate a biochemical basis for FEP-TAN and CTB-LED efficacy in KPC variant-mediated CAZ-AVI resistance backgrounds, whereby the boronate inhibitors have sufficient inhibitory activity, while FEP and CTB are poor substrates and bind to the variant enzymes with reduced affinity.

头孢吡肟-他尼波巴坦和头孢丁烯-利达波巴坦维持抗KPC变异的活性,导致头孢他啶-阿维巴坦耐药。
肺炎克雷伯菌碳青霉烯酶(KPCs)是广泛存在的β-内酰胺酶,是临床革兰氏阴性菌对碳青霉烯类和其他β-内酰胺类抗生素不敏感的主要原因。头孢他啶与β-内酰胺酶抑制剂阿维巴坦(CAZ-AVI)联合治疗KPC产生菌感染有效,但新出现的KPC变体使其对联合产生耐药性。Taniborbactam和leaborbactam是双环硼酸β-内酰胺酶抑制剂,目前分别与头孢吡肟和头孢布烯一起开发,用于治疗碳青霉烯耐药细菌感染。在这里,我们评估了临床上重要的KPC-2和KPC-3变体(V240G, D179Y和D179Y/T243M)对头孢吡肟-他尼波巴坦(FEP-TAN)和头孢丁烯-利达波巴坦(CTB-LED)抗菌活性的影响,并检测了这些变体的催化活性和抑制作用。与CAZ-AVI不同,FEP-TAN和CTB-LED对表达这些KPC变体的大肠杆菌具有高度活性。纯化酶实验表明,FEP和CTB被KPC变异体水解较差,对含有D179Y的变异体亲和力较弱。此外,KPC-2中D179Y的取代降低了TAN和LED的抑制作用,但这些抑制剂的失活效率(k2/K)显著高于AVI。含有d179y的KPC-3变异对K2/K的影响较小,TAN、LED和AVI观察到K2/K有很强的抑制作用。总之,这些发现说明了FEP- tan和CTB- led在KPC变异介导的CAZ-AVI抗性背景下的有效性的生化基础,其中硼酸抑制剂具有足够的抑制活性,而FEP和CTB是较差的底物,与变异酶结合的亲和力降低。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
求助全文
约1分钟内获得全文 求助全文
来源期刊
CiteScore
10.00
自引率
8.20%
发文量
762
审稿时长
3 months
期刊介绍: Antimicrobial Agents and Chemotherapy (AAC) features interdisciplinary studies that build our understanding of the underlying mechanisms and therapeutic applications of antimicrobial and antiparasitic agents and chemotherapy.
×
引用
GB/T 7714-2015
复制
MLA
复制
APA
复制
导出至
BibTeX EndNote RefMan NoteFirst NoteExpress
×
提示
您的信息不完整,为了账户安全,请先补充。
现在去补充
×
提示
您因"违规操作"
具体请查看互助需知
我知道了
×
提示
确定
请完成安全验证×
copy
已复制链接
快去分享给好友吧!
我知道了
右上角分享
点击右上角分享
0
联系我们:info@booksci.cn Book学术提供免费学术资源搜索服务,方便国内外学者检索中英文文献。致力于提供最便捷和优质的服务体验。 Copyright © 2023 布克学术 All rights reserved.
京ICP备2023020795号-1
ghs 京公网安备 11010802042870号
Book学术文献互助
Book学术文献互助群
群 号:481959085
Book学术官方微信