Aiello Daniel, Barnes Marjorie H, Biswas Esther E, Biswas Subhasis B, Gu Shen, Williams John D, Bowlin Terry L, Moir Donald T
Microbiotix, Inc, Worcester, MA 01605, USA.
Bioorg Med Chem. 2009 Jul 1;17(13):4466-76. doi: 10.1016/j.bmc.2009.05.014. Epub 2009 May 12.
Antibacterial compounds with new mechanisms of action are needed for effective therapy against drug-resistant pathogens in the clinic and in biodefense. Screens for inhibitors of the essential replicative helicases of Bacillus anthracis and Staphylococcus aureus yielded 18 confirmed hits (IC(50)25 microM). Several (5 of 18) of the inhibitors were also shown to inhibit DNA replication in permeabilized polA-deficient B. anthracis cells. One of the most potent inhibitors also displayed antibacterial activity (MIC approximately 5 microg/ml against a range of Gram-positive species including bacilli and staphylococci) together with good selectivity for bacterial versus mammalian cells (CC(50)/MIC>16) suitable for further optimization. This compound shares the bicyclic ring of the clinically proven aminocoumarin scaffold, but is not a gyrase inhibitor. It exhibits a mixed mode of helicase inhibition including a component of competitive inhibition with the DNA substrate (K(i)=8 microM) and is rapidly bactericidal at 4 x MIC.
临床上以及生物防御领域对抗耐药病原体进行有效治疗需要具有新作用机制的抗菌化合物。对炭疽芽孢杆菌和金黄色葡萄球菌必需复制解旋酶抑制剂的筛选产生了18个确认的命中物（IC(50)25 microM）。其中几种抑制剂（18种中的5种）还被证明可抑制通透化的polA缺陷型炭疽芽孢杆菌细胞中的DNA复制。最有效的抑制剂之一还表现出抗菌活性（对包括芽孢杆菌和葡萄球菌在内的一系列革兰氏阳性菌的MIC约为5微克/毫升），并且对细菌与哺乳动物细胞具有良好的选择性（CC(50)/MIC>16），适合进一步优化。该化合物与临床验证的氨基香豆素支架共享双环，但不是一种促旋酶抑制剂。它表现出解旋酶抑制的混合模式，包括与DNA底物的竞争性抑制成分（K(i)=8 microM），并且在4倍MIC时具有快速杀菌作用。
