Artola Marta, Ruiz-Avila Laura B, Vergoñós Albert, Huecas Sonia, Araujo-Bazán Lidia, Martín-Fontecha Mar, Vázquez-Villa Henar, Turrado Carlos, Ramírez-Aportela Erney, Hoegl Annabelle, Nodwell Matthew, Barasoain Isabel, Chacón Pablo, Sieber Stephan A, Andreu Jose M, López-Rodríguez María L
†Departamento de Química Orgánica I, Facultad de Ciencias Químicas, Universidad Complutense de Madrid, E-28040 Madrid, Spain.
‡Centro de Investigaciones Biológicas, CSIC, E-28040 Madrid, Spain.
ACS Chem Biol. 2015 Mar 20;10(3):834-43. doi: 10.1021/cb500974d. Epub 2014 Dec 30.
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 (Kd = 0.4-0.8 μM), display antibacterial activity against Gram-positive pathogenic bacteria, and show selectivity against tubulin. Biphenyl derivative 28 stands out as a potent FtsZ inhibitor (Kd = 0.5 μM) with high antibacterial activity [MIC (MRSA) = 7 μM]. 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.
必需细胞分裂蛋白FtsZ被认为是寻找具有新作用机制的抗菌药物以克服耐药性问题的一个有吸引力的靶点。FtsZ在细胞中部进行依赖于GTP的组装，形成Z环，这是一种动态结构，其不断演变直至细胞最终缢缩。因此，能够抑制其活性的分子最终将破坏细菌的生存能力。在这项工作中，我们报道了一系列能够取代GTP并特异性抑制FtsZ、阻断细菌分裂过程的小分子。这些新合成的抑制剂与FtsZ的GTP结合位点相互作用（解离常数Kd = 0.4 - 0.8 μM），对革兰氏阳性病原菌具有抗菌活性，并且对微管蛋白具有选择性。联苯衍生物28作为一种有效的FtsZ抑制剂（Kd = 0.5 μM）脱颖而出，具有高抗菌活性[耐甲氧西林金黄色葡萄球菌（MRSA）的最低抑菌浓度MIC = 7 μM]。对化合物22、28、33和36作用机制的深入分析表明，它们作为正确FtsZ组装的有效抑制剂，阻断细菌分裂，从而导致丝状未分裂细胞的形成。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，并为具有新作用机制的抗生素打开了大门。
