1. Discovery and Hit-to-Lead Optimization of Benzothiazole Scaffold- Based DNA Gyrase Inhibitors with Potent Activity against Acinetobacter baumannii and Pseudomonas aeruginosa
- Author
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Cotman, Andrej Emanuel, Durcik, Martina, Tiz, Davide Benedetto, Fulgheri, Federica, Secci, Daniela, Sterle, Masa, Mozina, Stefan, Skok, Ziga, Zidar, Nace, Zega, Anamarija, Ilas, Janez, Masic, Lucija Peterlin, Tomasic, Tihomir, Hughes, Diarmaid, Huseby, Douglas L., Cao, Sha, Garoff, Linnea, Fernandez, Talia Berruga, Giachou, Paraskevi, Crone, Lisa, Simoff, Ivailo, Svensson, Richard, Birnir, Bryndis, Korol, Sergiy, Jin, Zhe, Vicente, Francisca, Ramos, Maria C., de la Cruz, Mercedes, Glinghammar, Bjorn, Lenhammar, Lena, Henderson, Sara R., Mundy, Julia E. A., Maxwell, Anthony, Stevenson, Clare E. M., Lawson, David M., Janssen, Guido V., Sterk, Geert Jan, Kikelj, Danijel, Cotman, Andrej Emanuel, Durcik, Martina, Tiz, Davide Benedetto, Fulgheri, Federica, Secci, Daniela, Sterle, Masa, Mozina, Stefan, Skok, Ziga, Zidar, Nace, Zega, Anamarija, Ilas, Janez, Masic, Lucija Peterlin, Tomasic, Tihomir, Hughes, Diarmaid, Huseby, Douglas L., Cao, Sha, Garoff, Linnea, Fernandez, Talia Berruga, Giachou, Paraskevi, Crone, Lisa, Simoff, Ivailo, Svensson, Richard, Birnir, Bryndis, Korol, Sergiy, Jin, Zhe, Vicente, Francisca, Ramos, Maria C., de la Cruz, Mercedes, Glinghammar, Bjorn, Lenhammar, Lena, Henderson, Sara R., Mundy, Julia E. A., Maxwell, Anthony, Stevenson, Clare E. M., Lawson, David M., Janssen, Guido V., Sterk, Geert Jan, and Kikelj, Danijel
- Abstract
We have developed compounds with a promising activity against Acinetobacter baumannii and Pseudomonas aerugi-nosa, which are both on the WHO priority list of antibiotic -resistant bacteria. Starting from DNA gyrase inhibitor 1, we identified compound 27, featuring a 10-fold improved aqueous solubility, a 10-fold improved inhibition of topoisomerase IV from A. baumannii and P. aeruginosa, a 10-fold decreased inhibition of human topoisomerase II alpha, and no cross-resistance to novobiocin. Cocrystal structures of 1 in complex with Escherichia coli GyrB24 and (S)-27 in complex with A. baumannii GyrB23 and P. aeruginosa GyrB24 revealed their binding to the ATP-binding pocket of the GyrB subunit. In further optimization steps, solubility, plasma free fraction, and other ADME properties of 27 were improved by fine-tuning of lipophilicity. In particular, analogs of 27 with retained anti-Gram-negative activity and improved plasma free fraction were identified. The series was found to be nongenotoxic, nonmutagenic, devoid of mitochondrial toxicity, and possessed no ion channel liabilities.
- Published
- 2023
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