Insights into the Spectrum of Activity and Mechanism of Action of MGB-BP-3.
Insights into the Spectrum of Activity and Mechanism of Action of MGB-BP-3.
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DOI：
10.1021/acsinfecdis.2c00445
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发表时间：
2022-12-09
影响因子：
5.3
通讯作者：
Scott, Fraser J.
中科院分区：
文献类型：
--
作者：
Hind, Charlotte;Clifford, Melanie;Woolley, Charlotte;Harmer, Jane;McGee, Leah M. C.;Tyson-Hirst, Izaak;Tait, Henry J.;Brooke, Daniel P.;Dancer, Stephanie J.;Hunter, Iain S.;Suckling, Colin J.;Beveridge, Rebecca;Parkinson, John A.;Sutton, J. Mark;Scott, Fraser J.
MGB-BP-3是一种潜在的一流抗生素，一种斯特拉斯克莱德小槽粘合剂(S-MGB)，已成功完成治疗艰难梭菌相关疾病的IIa期临床试验。其确切的作用机制和抗革兰氏阴性病原体活性有限的原因相对未知。在这里，单独使用MGB-BP-3治疗显著抑制革兰氏阳性细菌的生长，但不是像预期的那样抑制革兰氏阴性细菌的生长。协同作用分析表明，低效率的细胞内蓄积，通过渗透和外排，可能是缺乏革兰氏阴性菌活性的原因。紫外-可见(UV-Vis)热熔法和荧光插层置换实验表明，在革兰氏阴性和革兰氏阳性细菌中，MGB-BP-3与其胞内靶标DNA都有很强的相互作用。纳米电喷雾电离质谱仪和核磁共振波谱证实了MGB-BP-3以二聚体的形式与dsDNA结合。II型细菌拓扑异构酶抑制实验表明，MGB-BP-3能干扰金黄色葡萄球菌和大肠杆菌的旋转酶的超卷绕作用和拓扑异构酶IV的松弛和去活作用。然而，没有观察到切割复合体稳定的证据，例如对于氟喹诺酮类药物，在大肠杆菌报告菌株中没有诱导DSB和SOS反应的证实。这些结果突出了MGB-BP-3的其他作用机制，包括干扰II型细菌拓扑异构酶的作用。虽然MGB-BP-3‘S缺乏革兰氏阴性活性，并对此提出了理解，但认识到MGB-BP-3可以靶向革兰氏阴性生物的dna，这将使进一步的设计迭代能够实现革兰氏阴性活性S-MGB。
MGB-BP-3 is a potential first-in-class antibiotic, a Strathclyde Minor Groove Binder (S-MGB), that has successfully completed Phase IIa clinical trials for the treatment of Clostridioides difficile associated disease. Its precise mechanism of action and the origin of limited activity against Gram-negative pathogens are relatively unknown. Herein, treatment with MGB-BP-3 alone significantly inhibited the bacterial growth of the Gram-positive, but not Gram-negative, bacteria as expected. Synergy assays revealed that inefficient intracellular accumulation, through both permeation and efflux, is the likely reason for lack of Gram-negative activity. MGB-BP-3 has strong interactions with its intracellular target, DNA, in both Gram-negative and Gram-positive bacteria, revealed through ultraviolet–visible (UV–vis) thermal melting and fluorescence intercalator displacement assays. MGB-BP-3 was confirmed to bind to dsDNA as a dimer using nano-electrospray ionization mass spectrometry and nuclear magnetic resonance (NMR) spectroscopy. Type II bacterial topoisomerase inhibition assays revealed that MGB-BP-3 was able to interfere with the supercoiling action of gyrase and the relaxation and decatenation actions of topoisomerase IV of both Staphylococcus aureus and Escherichia coli. However, no evidence of stabilization of the cleavage complexes was observed, such as for fluoroquinolones, confirmed by a lack of induction of DSBs and the SOS response in E. coli reporter strains. These results highlight additional mechanisms of action of MGB-BP-3, including interference of the action of type II bacterial topoisomerases. While MGB-BP-3′s lack of Gram-negative activity was confirmed, and an understanding of this presented, the recognition that MGB-BP-3 can target DNA of Gram-negative organisms will enable further iterations of design to achieve a Gram-negative active S-MGB.
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影响因子：
3.7
作者：
Lamers RP;Cavallari JF;Burrows LL
通讯作者：
Burrows LL
影响因子：
6.7
作者：
Scott, Fraser J.;Nichol, Ryan J. O.;Suckling, Colin J.
通讯作者：
Suckling, Colin J.
影响因子：
--
作者：
Suckling, Colin J;Hunter, Iain S;Scott, Fraser J
通讯作者：
Scott, Fraser J
DOI：
10.1073/pnas.82.5.1376
发表时间：
1985-01-01
影响因子：
11.1
作者：
KOPKA, ML;YOON, C;DICKERSON, RE
通讯作者：
DICKERSON, RE
影响因子：
7.3
作者：
Giordani, Federica;Khalaf, Abedawn I.;Scott, Fraser J.
通讯作者：
Scott, Fraser J.