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Discovery and Hit-to-Lead Optimization of Benzothiazole Scaffold-Based DNA Gyrase Inhibitors with Potent Activity against Acinetobacter baumannii and Pseudomonas aeruginosa

[Image: see text] We have developed compounds with a promising activity against Acinetobacter baumannii and Pseudomonas aeruginosa, 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...

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Autores principales: Cotman, Andrej Emanuel, Durcik, Martina, Benedetto Tiz, Davide, Fulgheri, Federica, Secci, Daniela, Sterle, Maša, Možina, Štefan, Skok, Žiga, Zidar, Nace, Zega, Anamarija, Ilaš, Janez, Peterlin Mašič, Lucija, Tomašič, Tihomir, Hughes, Diarmaid, Huseby, Douglas L., Cao, Sha, Garoff, Linnéa, Berruga Fernández, Talía, Giachou, Paraskevi, Crone, Lisa, Simoff, Ivailo, Svensson, Richard, Birnir, Bryndis, Korol, Sergiy V., Jin, Zhe, Vicente, Francisca, Ramos, Maria C., de la Cruz, Mercedes, Glinghammar, Björn, 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
Formato: Online Artículo Texto
Lenguaje:English
Publicado: American Chemical Society 2023
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9884090/
https://www.ncbi.nlm.nih.gov/pubmed/36634346
http://dx.doi.org/10.1021/acs.jmedchem.2c01597
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author Cotman, Andrej Emanuel
Durcik, Martina
Benedetto Tiz, Davide
Fulgheri, Federica
Secci, Daniela
Sterle, Maša
Možina, Štefan
Skok, Žiga
Zidar, Nace
Zega, Anamarija
Ilaš, Janez
Peterlin Mašič, Lucija
Tomašič, Tihomir
Hughes, Diarmaid
Huseby, Douglas L.
Cao, Sha
Garoff, Linnéa
Berruga Fernández, Talía
Giachou, Paraskevi
Crone, Lisa
Simoff, Ivailo
Svensson, Richard
Birnir, Bryndis
Korol, Sergiy V.
Jin, Zhe
Vicente, Francisca
Ramos, Maria C.
de la Cruz, Mercedes
Glinghammar, Björn
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
author_facet Cotman, Andrej Emanuel
Durcik, Martina
Benedetto Tiz, Davide
Fulgheri, Federica
Secci, Daniela
Sterle, Maša
Možina, Štefan
Skok, Žiga
Zidar, Nace
Zega, Anamarija
Ilaš, Janez
Peterlin Mašič, Lucija
Tomašič, Tihomir
Hughes, Diarmaid
Huseby, Douglas L.
Cao, Sha
Garoff, Linnéa
Berruga Fernández, Talía
Giachou, Paraskevi
Crone, Lisa
Simoff, Ivailo
Svensson, Richard
Birnir, Bryndis
Korol, Sergiy V.
Jin, Zhe
Vicente, Francisca
Ramos, Maria C.
de la Cruz, Mercedes
Glinghammar, Björn
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
author_sort Cotman, Andrej Emanuel
collection PubMed
description [Image: see text] We have developed compounds with a promising activity against Acinetobacter baumannii and Pseudomonas aeruginosa, 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 IIα, 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.
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spelling pubmed-98840902023-01-29 Discovery and Hit-to-Lead Optimization of Benzothiazole Scaffold-Based DNA Gyrase Inhibitors with Potent Activity against Acinetobacter baumannii and Pseudomonas aeruginosa Cotman, Andrej Emanuel Durcik, Martina Benedetto Tiz, Davide Fulgheri, Federica Secci, Daniela Sterle, Maša Možina, Štefan Skok, Žiga Zidar, Nace Zega, Anamarija Ilaš, Janez Peterlin Mašič, Lucija Tomašič, Tihomir Hughes, Diarmaid Huseby, Douglas L. Cao, Sha Garoff, Linnéa Berruga Fernández, Talía Giachou, Paraskevi Crone, Lisa Simoff, Ivailo Svensson, Richard Birnir, Bryndis Korol, Sergiy V. Jin, Zhe Vicente, Francisca Ramos, Maria C. de la Cruz, Mercedes Glinghammar, Björn 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 J Med Chem [Image: see text] We have developed compounds with a promising activity against Acinetobacter baumannii and Pseudomonas aeruginosa, 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 IIα, 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. American Chemical Society 2023-01-12 /pmc/articles/PMC9884090/ /pubmed/36634346 http://dx.doi.org/10.1021/acs.jmedchem.2c01597 Text en © 2023 The Authors. Published by American Chemical Society https://creativecommons.org/licenses/by/4.0/Permits the broadest form of re-use including for commercial purposes, provided that author attribution and integrity are maintained (https://creativecommons.org/licenses/by/4.0/).
spellingShingle Cotman, Andrej Emanuel
Durcik, Martina
Benedetto Tiz, Davide
Fulgheri, Federica
Secci, Daniela
Sterle, Maša
Možina, Štefan
Skok, Žiga
Zidar, Nace
Zega, Anamarija
Ilaš, Janez
Peterlin Mašič, Lucija
Tomašič, Tihomir
Hughes, Diarmaid
Huseby, Douglas L.
Cao, Sha
Garoff, Linnéa
Berruga Fernández, Talía
Giachou, Paraskevi
Crone, Lisa
Simoff, Ivailo
Svensson, Richard
Birnir, Bryndis
Korol, Sergiy V.
Jin, Zhe
Vicente, Francisca
Ramos, Maria C.
de la Cruz, Mercedes
Glinghammar, Björn
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
Discovery and Hit-to-Lead Optimization of Benzothiazole Scaffold-Based DNA Gyrase Inhibitors with Potent Activity against Acinetobacter baumannii and Pseudomonas aeruginosa
title Discovery and Hit-to-Lead Optimization of Benzothiazole Scaffold-Based DNA Gyrase Inhibitors with Potent Activity against Acinetobacter baumannii and Pseudomonas aeruginosa
title_full Discovery and Hit-to-Lead Optimization of Benzothiazole Scaffold-Based DNA Gyrase Inhibitors with Potent Activity against Acinetobacter baumannii and Pseudomonas aeruginosa
title_fullStr Discovery and Hit-to-Lead Optimization of Benzothiazole Scaffold-Based DNA Gyrase Inhibitors with Potent Activity against Acinetobacter baumannii and Pseudomonas aeruginosa
title_full_unstemmed Discovery and Hit-to-Lead Optimization of Benzothiazole Scaffold-Based DNA Gyrase Inhibitors with Potent Activity against Acinetobacter baumannii and Pseudomonas aeruginosa
title_short Discovery and Hit-to-Lead Optimization of Benzothiazole Scaffold-Based DNA Gyrase Inhibitors with Potent Activity against Acinetobacter baumannii and Pseudomonas aeruginosa
title_sort discovery and hit-to-lead optimization of benzothiazole scaffold-based dna gyrase inhibitors with potent activity against acinetobacter baumannii and pseudomonas aeruginosa
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9884090/
https://www.ncbi.nlm.nih.gov/pubmed/36634346
http://dx.doi.org/10.1021/acs.jmedchem.2c01597
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