There is an urgent need for new antimicrobials to treat the opportunistic Gram-negative Burkholderia cenocepacia, which represents a problematic challenge for cystic fibrosis patients. Recently, a benzothiadiazole derivative, C109, was shown to be effective against the infections caused by B. cenocepacia and other Gram-negative and-positive bacteria. C109 has a promising cellular target, the cell division protein FtsZ, and a recently developed PEGylated formulation make it an attractive molecule to counteract Burkholderia infections. However, the ability of efflux pumps to extrude it out of the cell represents a limitation for its use. Here, more than 50 derivatives of C109 were synthesized and tested against Gram-negative species and the Gram-positive Staphylococcus aureus. In addition, their activity was evaluated on the purified FtsZ protein. The chemical, metabolic and cellular stability of C109 has been assayed using different biological systems, including quantitative single-cell imaging. However, no further improvement on C109 was achieved, and the role of efflux in resistance was further confirmed. Also, a novel nitroreductase that can inactivate the compound was characterized, but it does not appear to play a role in natural resistance. All these data allowed a deep characterization of the compound, which will contribute to a further improvement of its properties.

中文翻译：

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FtsZ抑制剂有效对抗Burkholderia cenocepacia的化学，代谢和细胞表征。

迫切需要新的抗生素来治疗机会性革兰氏阴性伯克霍尔德氏菌新陈代谢，这对于囊性纤维化患者是一个有挑战性的挑战。最近，苯并噻二唑衍生物C109被证明可有效抵抗由新细菌，其他革兰氏阴性和阳性细菌引起的感染。C109具有理想的细胞靶标，细胞分裂蛋白FtsZ，最近开发的PEG化制剂使其成为抵抗伯克霍尔德氏菌感染的诱人分子。然而，外排泵将其挤出细胞的能力代表了其使用的限制。在这里，合成了C109的50多种衍生物，并针对革兰氏阴性菌和革兰氏阳性金黄色葡萄球菌进行了测试。另外，在纯化的FtsZ蛋白上评估了它们的活性。已使用不同的生物系统，包括定量单细胞成像，对C109的化学，代谢和细胞稳定性进行了测定。但是，没有对C109进行进一步的改进，并且进一步证实了外排在抗性中的作用。而且，表征了可以使化合物失活的新型硝基还原酶，但是它似乎没有在天然抗性中起作用。所有这些数据可以对化合物进行深入的表征，这将有助于进一步改善其性能。可以使该化合物失活的新型硝基还原酶已被表征，但它似乎并未在天然抗性中起作用。所有这些数据可以对化合物进行深入的表征，这将有助于进一步改善其性能。可以使该化合物失活的新型硝基还原酶已被表征，但它似乎并未在天然抗性中起作用。所有这些数据可以对化合物进行深入的表征，这将有助于进一步改善其性能。