Covalent DNA Binding Is Essential for Gram-Negative Antibacterial Activity of Broad Spectrum Pyrrolobenzodiazepines.
Covalent DNA Binding Is Essential for Gram-Negative Antibacterial Activity of Broad Spectrum Pyrrolobenzodiazepines.
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DOI：
10.3390/antibiotics11121770
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发表时间：
2022-12-07
影响因子：
4.8
通讯作者：
Rahman, Khondaker Miraz
中科院分区：
文献类型：
--
作者：
Picconi, Pietro;Hind, Charlotte K.;Sutton, J. Mark;Rahman, Khondaker Miraz
关键词：
在过去的50年里，发现新的抗生素类别的速度一直非常缓慢，因此迫切需要找到新的抗生素类别来对抗多重耐药细菌。近年来，具有C8连接的脂肪族杂环的吡咯氯苯并二氮杂环类化合物被鉴定为一类新的广谱抗生素类，具有抗革兰氏阴性菌的活性。将已报道的吡咯洛苯并二氮杂铅化合物的活性亚胺部分用酰胺取代，得到非DNA结合、无细胞毒性的地拉坦类似物，以进一步了解其构效关系，提高该类化合物的安全性。合成的化合物被用来对抗多重耐药的革兰氏阳性和革兰氏阴性细菌，包括世卫组织优先病原体。地拉坦类似物对耐多药革兰氏阳性菌的最低抑菌浓度为4~32 mg/L，亚胺类似物的最低抑菌浓度为0.03~2 mg/L。同时，发现它们对耐多药革兰氏阴性菌没有活性，最低抑菌浓度为32毫克/L，而亚胺类似物的最低抑菌浓度为0.5-32毫克/L。一项分子模拟研究表明，亚胺功能的缺乏也影响了PBDS与DNA旋转酶的相互作用。这项研究表明，N10-C11亚胺部分的存在对吡咯洛苯并二氮卓类化合物的广谱活性至关重要。
It is urgent to find new antibiotic classes against multidrug-resistant bacteria as the rate of discovery of new classes of antibiotics has been very slow in the last 50 years. Recently, pyrrolobenzodiazepines (PBDs) with a C8-linked aliphatic-heterocycle have been identified as a new broad-spectrum antibiotic class with activity against Gram-negative bacteria. The active imine moiety of the reported lead pyrrolobenzodiazepine compounds was replaced with amide to obtain the non-DNA binding and noncytotoxic dilactam analogues to understand the structure-activity relationship further and improve the safety potential of this class. The synthesised compounds were tested against panels of multidrug-resistant Gram-positive and Gram-negative bacteria, including WHO priority pathogens. Minimum inhibitory concentrations for the dilactam analogues ranged from 4 to 32 mg/L for MDR Gram-positive bacteria, compared to 0.03 to 2 mg/L for the corresponding imine analogues. At the same time, they were found to be inactive against MDR Gram-negative bacteria, with a MIC > 32 mg/L, compared to a MIC of 0.5 to 32 mg/L for imine analogues. A molecular modelling study suggests that the lack of imine functionality also affects the interaction of PBDs with DNA gyrase. This study suggests that the presence of N10-C11 imine moiety is crucial for the broad-spectrum activity of pyrrolobenzodiazepines.
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影响因子：
16.6
作者：
Mantaj, Julia;Jackson, Paul J. M.;Rahman, Khondaker M.;Thurston, David E.
通讯作者：
Thurston, David E.
影响因子：
2.7
作者：
Donnell, Andrew F.;Zhang, Yong;Gangwar, Sanjeev
通讯作者：
Gangwar, Sanjeev
影响因子：
3.5
作者：
Antonow, Dyeison;Jenkins, Terence C.;Thurston, David E.
通讯作者：
Thurston, David E.
影响因子：
7.3
作者：
Gregson, Stephen J.;Masterson, Luke A.;Howard, Philip W.
通讯作者：
Howard, Philip W.
DOI：
10.1016/j.ddtec.2018.10.004
发表时间：
2018-12-01
期刊：
Drug discovery today. Technologies
影响因子：
--
作者：
Jackson, Paul J M;Kay, Syafiq;Thurston, David E
通讯作者：
Thurston, David E