Effective GTP-Replacing FtsZ Inhibitors and Antibacterial Mechanism of Action
Effective GTP-Replacing FtsZ Inhibitors and Antibacterial Mechanism of Action
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DOI：
10.1021/cb500974d
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发表时间：
2015-03-01
影响因子：
4
通讯作者：
Lopez-Rodriguez, Maria L.
中科院分区：
文献类型：
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作者：
Artola, Marta;Ruiz-Avila, Laura B.;Lopez-Rodriguez, Maria L.
必需细胞分裂蛋白FtsZ被认为是寻找具有新的作用机制的抗细菌药物来克服耐药性问题的一个有吸引力的目标。FtsZ在细胞中间经过gtp依赖的组装形成z环，这是一个动态结构，直到细胞最终收缩。因此，能够抑制其活性的分子最终会破坏细菌的生存能力。在这项工作中，我们报道了一系列新的小分子能够替代GTP并特异性抑制FtsZ，阻断细菌分裂过程。这些新合成的抑制剂与FtsZ的gtp结合位点（K-d = 0.4 ~ 0.8 μ M）相互作用，对革兰氏阳性致病菌表现出抗菌活性，对微管蛋白表现出选择性。联苯衍生物28是一种有效的FtsZ抑制剂（K-d = 0.5 μ M），具有较高的抗菌活性[MIC (MRSA) = 7 μ M]。对化合物22、28、33和36的作用机制的深入分析表明，它们是FtsZ正确组装的有效抑制剂，阻止细菌分裂，从而导致丝状未分裂细胞。这些发现为开发靶向gtp结合位点的化合物作为抗菌剂提供了令人信服的理论依据，并为开发具有新作用机制的抗生素打开了大门。
Essential cell division protein FtsZ is considered an attractive target in the search for antibacterials with novel mechanisms of action to overcome the resistance problem. FtsZ undergoes GTP-dependent assembly at midcell to form the Z-ring, a dynamic structure that evolves until final constriction of the cell. Therefore, molecules able to inhibit its activity will eventually disrupt bacterial viability. In this work, we report a new series of small molecules able to replace GTP and to specifically inhibit FtsZ, blocking the bacterial division process. These new synthesized inhibitors interact with the GTP-binding site of FtsZ (K-d = 0.4-0.8 mu M), display antibacterial activity against Gram-positive pathogenic bacteria, and show selectivity against tubulin. Biphenyl derivative 28 stands out as a potent FtsZ inhibitor (K-d = 0.5 mu M) with high antibacterial activity [MIC (MRSA) = 7 mu M]. In-depth analysis of the mechanism of action of compounds 22, 28, 33, and 36 has revealed that they act as effective inhibitors of correct FtsZ assembly, blocking bacterial division and thus leading to filamentous undivided cells. These findings provide a compelling rationale for the development of compounds targeting the GTP-binding site as antibacterial agents and open the door to antibiotics with novel mechanisms of action.