De novo design of type II topoisomerase inhibitors as potential antimicrobial agents targeting a novel binding region.
De novo design of type II topoisomerase inhibitors as potential antimicrobial agents targeting a novel binding region.
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DOI：
10.1039/d2md00049k
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发表时间：
2022-07-20
影响因子：
4.1
通讯作者：
中科院分区：
文献类型：
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作者：
预计到 2050 年，抗菌药物耐药性将导致全球每年 1000 万人死亡，比癌症死亡人数还多，给世界经济造成 100 万亿美元的损失。显然，解决这个问题的策略至关重要，因为细菌进化使我们当前的抗生素失效。在已建立的抗菌靶 DNA 旋转酶上发现变构结合位点提供了一种新的药物化学策略。由于该位点与氟喹诺酮结合位点不同，因此尚未记录耐药性。受已发表的基于噻吩的变构抑制剂的启发，我们利用计算机分子设计方法设计并合成了一系列新型联苯抑制剂。该系列在体外针对大肠杆菌 DNA 旋转酶和大肠杆菌拓扑异构酶 IV 进行了评估，其中最有效的化合物对 DNA 旋转酶表现出低微摩尔范围的 IC50 值，并且针对拓扑异构酶 IV 的活性仅低约 2 倍。本文报道的结构-活性关系表明了进一步利用该变构位点的见解，提供了克服氟喹诺酮耐药性的途径。使用计算设计、制造和测试策略来鉴定细菌 DNA 旋转酶和拓扑异构酶 IV 的抗菌抑制剂，建议在新的变构位点结合。
By 2050, it is predicted that antimicrobial resistance will be responsible for 10 million global deaths annually, more deaths than cancer, costing the world economy $100 trillion. Clearly, strategies to address this problem are essential as bacterial evolution is rendering our current antibiotics ineffective. The discovery of an allosteric binding site on the established antibacterial target DNA gyrase offers a new medicinal chemistry strategy. As this site is distinct from the fluoroquinolone binding site, resistance is not yet documented. Using in silico molecular design methods, we have designed and synthesised a novel series of biphenyl-based inhibitors inspired by a published thiophene-based allosteric inhibitor. This series was evaluated in vitro against Escherichia coli DNA gyrase and E. coli topoisomerase IV with the most potent compounds exhibiting IC50 values towards the low micromolar range for DNA gyrase and only ∼2-fold less active against topoisomerase IV. The structure–activity relationships reported herein suggest insights to further exploit this allosteric site, offering a pathway to overcome developing fluoroquinolone resistance. A computational design, make and test strategy was used to identify antibacterial inhibitors of bacterial DNA gyrase and topoisomerase IV, proposed to bind at a novel allosteric site.
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DOI：
10.1073/pnas.85.19.7177
发表时间：
1988-10-01
影响因子：
11.1
作者：
TSAIPFLUGFELDER, M;LIU, LF;WANG, JC
通讯作者：
WANG, JC
DOI：
10.1016/s0140-6736(21)02724-0
发表时间：
2022-02-12
期刊：
Lancet (London, England)
影响因子：
--
作者：
Antimicrobial Resistance Collaborators
通讯作者：
Antimicrobial Resistance Collaborators
DOI：
10.1073/pnas.1700721114
发表时间：
2017-05-30
影响因子：
11.1
作者：
Chan, Pan F.;Germe, Thomas;Stavenger, Robert A.
通讯作者：
Stavenger, Robert A.
DOI：
10.3390/molecules25235662
发表时间：
2020-12-01
期刊：
Molecules (Basel, Switzerland)
影响因子：
--
作者：
Bush NG;Diez-Santos I;Abbott LR;Maxwell A
通讯作者：
Maxwell A
影响因子：
4.2
作者：
McPhillie, Martin J.;Trowbridge, Rachel;Fishwick, Colin W. G.
通讯作者：
Fishwick, Colin W. G.