Penicillin-Binding Protein Occupancy Dataset for 18 β-Lactams and 4 β-Lactamase Inhibitors in Neisseria gonorrhoeae.
Penicillin-Binding Protein Occupancy Dataset for 18 β-Lactams and 4 β-Lactamase Inhibitors in Neisseria gonorrhoeae.
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淋病奈瑟菌中 18 种 β-内酰胺和 4 种 β-内酰胺酶抑制剂的青霉素结合蛋白占用数据集。
DOI：
10.1128/spectrum.00692-23
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发表时间：
2023-06-15
影响因子：
3.7
通讯作者：
中科院分区：
文献类型：
--
作者：
缺乏针对淋病奈瑟菌的有效一线抗生素治疗以及耐药菌株在全球范围内的传播是全球健康危机恶化的主要驱动因素。β-内酰胺类抗生素已成为抗淋球菌治疗药物的支柱。然而，我们缺乏关键的见解来设计合理优化的疗法。在目前的工作中，我们在两个N.淋病ATCC型收集菌株，19424和49226（PBP 2 XXII型和A39 T mtrR变化）。在分离的膜制备物中通过Bocillin FL结合试验测定PBP结合（IC 50）。鉴别了三组差异PBP IC 50，并且在两种菌株中大部分一致，但存在定量差异。碳青霉烯类对PBP 2和PBP 3具有共选择性（0.01 ~ 0.03 mg/L）。第三代和第四代头孢菌素头孢克肟、头孢噻肟、头孢他啶、头孢吡肟和头孢曲松对PBP 2的IC 50值最低（0.01 mg/L），而头孢西丁、头孢洛林和头孢洛扎需要较高的浓度（0.04至>2 mg/L）。在两种菌株中，氨曲南对PBP 2具有选择性（0.03至0.07 mg/L）;氨地西林在较高浓度（1.33至2.94 mg/L）下结合该PBP。青霉素在菌株ATCC 19424中特异性靶向PBP 2（0.02至0.19 mg/L），并且在菌株ATCC 49226中显示出有限的抑制（0.01至>2 mg/L）。基于β-内酰胺的β-内酰胺酶抑制剂舒巴坦和他唑巴坦（1.07 - 6.02 mg/L）观察到优先结合PBP 2;同时，二氮杂双环辛烷抑制剂曲马巴坦和阿维巴坦对PBP 3具有选择性（1.27 - 5.40 mg/L）。该数据集将为未来的研究设定标准，这将有助于合理使用和转化开发抗生素对抗多药耐药（MDR）N。淋病重要性手稿代表了第一个N。淋病PBP结合数据集的22种化学不同的药物在两种类型的菌株具有不同的遗传背景。我们已经根据其PBP结合IC 50确定了三个药物簇，并强调了所研究的两种菌株之间的结合差异。利用目前可用的基因组信息和PBP结合数据，我们已经能够将目标实现差异和影响药物摄取的突变与MIC变化相关联。目前工作的结果将使我们能够开发出非常实用的分子工具，用于研究和设计新的合理设计的疗法，能够对抗日益增长的MDR淋球菌威胁。
The lack of effective first-line antibiotic treatments against Neisseria gonorrhoeae, and the worldwide dissemination of resistant strains, are the main drivers of a worsening global health crisis. β-lactam antibiotics have been the backbone of therapeutic armamentarium against gonococci. However, we are lacking critical insights to design rationally optimized therapies. In the present work, we generated the first PBP-binding data set on 18 currently available and clinically relevant β-lactams and 4 β-lactamase inhibitors in two N. gonorrhoeae ATCC type collection strains, 19424 and 49226 (PBP2 type XXII and A39T change in mtrR). PBP binding (IC50) was determined via the Bocillin FL binding assay in isolated membrane preparations. Three clusters of differential PBP IC50s were identified and were mostly consistent across both strains, but with quantitative differences. Carbapenems were coselective for PBP2 and PBP3 (0.01 to 0.03 mg/L). Third- and fourth-generation cephalosporins cefixime, cefotaxime, ceftazidime, cefepime, and ceftriaxone showed the lowest IC50 values for PBP2 (0.01 mg/L), whereas cefoxitin, ceftaroline, and ceftolozane required higher concentrations (0.04 to >2 mg/L). Aztreonam was selective for PBP2 in both strains (0.03 to 0.07 mg/L); amdinocillin bound this PBP at higher concentrations (1.33 to 2.94 mg/L). Penicillins specifically targeted PBP2 in strain ATCC 19424 (0.02 to 0.19 mg/L) and showed limited inhibition in strain ATCC 49226 (0.01 to >2 mg/L). Preferential PBP2 binding was observed by β-lactam-based β-lactamase inhibitors sulbactam and tazobactam (1.07 to 6.02 mg/L); meanwhile, diazabicyclooctane inhibitors relebactam and avibactam were selective for PBP3 (1.27 to 5.40 mg/L). This data set will set the bar for future studies that will help the rational use and translational development of antibiotics against multidrug-resistant (MDR) N. gonorrhoeae. IMPORTANCE The manuscript represents the first N. gonorrhoeae PBP-binding data set for 22 chemically different drugs in two type strains with different genetic background. We have identified three clusters of drugs according to their PBP binding IC50s and highlighted the binding differences across the two strains studied. With the currently available genomic information and the PBP-binding data, we have been able to correlate the target attainment differences and the mutations that affect the drug uptake with the MIC changes. The results of the current work will allow us to develop molecular tools of great practical use for the study and the design of new rationally designed therapies capable of combating the growing MDR gonococci threat.
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影响因子：
11.8
作者：
Lahra MM;Martin I;Demczuk W;Jennison AV;Lee KI;Nakayama SI;Lefebvre B;Longtin J;Ward A;Mulvey MR;Wi T;Ohnishi M;Whiley D
通讯作者：
Whiley D
影响因子：
3.2
作者：
Beggs, Grace A.;Zalucki, Yaramah M.;Brennan, Richard G.
通讯作者：
Brennan, Richard G.
影响因子：
3
作者：
Fuchs, Frieder;Wille, Julia;Higgins, Paul G.
通讯作者：
Higgins, Paul G.
影响因子：
11.8
作者：
Hook, Edward W., III;Newman, Lori;Deal, Carolyn
通讯作者：
Deal, Carolyn
影响因子：
3.2
作者：
Dougherty, TJ;Kennedy, K;Pucci, MJ
通讯作者：
Pucci, MJ