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

Andrej Emanuel Cotman; Martina Durcik; Davide Benedetto Tiz; Federica Fulgheri; Daniela Secci; Maša Sterle; Štefan Možina; Žiga Skok; Nace Zidar; Anamarija Zega; Janez Ilaš; Lucija Peterlin Mašič; Tihomir Tomašič; Diarmaid Hughes; Douglas L. Huseby; Sha Cao; Linnéa Garoff; Talía Berruga Fernández; Paraskevi Giachou; Lisa Crone; Ivailo Simoff; Richard Svensson; Bryndis Birnir; Sergiy V. Korol; Zhe Jin; Francisca Vicente; Maria C. Ramos; Mercedes De La Cruz; Björn Glinghammar; Lena Lenhammar; Sara R. Henderson; Julia E.A. Mundy; Anthony Maxwell; Clare E.M. Stevenson; David M. Lawson; Guido V. Janssen; Geert Jan Sterk; Danijel Kikelj

doi:10.1021/acs.jmedchem.2c01597

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

Andrej Emanuel Cotman, Martina Durcik, Davide Benedetto Tiz, Federica Fulgheri, Daniela Secci, Maša Sterle, Štefan Možina, Žiga Skok, Nace Zidar, Anamarija Zega, Janez Ilaš, Lucija Peterlin Mašič, Tihomir Tomašič, Diarmaid Hughes, Douglas L. Huseby, Sha Cao, Linnéa Garoff, Talía Berruga Fernández, Paraskevi Giachou, Lisa CroneIvailo Simoff, Richard Svensson, Bryndis Birnir, Sergiy V. Korol, Zhe Jin, Francisca Vicente, Maria C. Ramos, Mercedes De La Cruz, Björn Glinghammar, Lena Lenhammar, Sara R. Henderson, Julia E.A. Mundy, Anthony Maxwell, Clare E.M. Stevenson, David M. Lawson, Guido V. Janssen, Geert Jan Sterk, Danijel Kikelj^*

^*Corresponding author for this work

Research output: Contribution to Journal › Article › Academic › peer-review

Abstract

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.

Original language	English
Pages (from-to)	1380-1425
Number of pages	46
Journal	Journal of medicinal chemistry
Volume	66
Issue number	2
Early online date	12 Jan 2023
DOIs	https://doi.org/10.1021/acs.jmedchem.2c01597
Publication status	Published - 26 Jan 2023

Bibliographical note

Funding Information:
The research presented in this paper was conducted as part of the ND4BB ENABLE Consortium and has received support from the Innovative Medicines Initiative Joint Undertaking under grant no. 115583, resources of which are comprised of financial contributions from the European Union’s seventh framework program (FP7/2007-2013) and EFPIA companies’ in-kind contribution. The views expressed in this article are the views of the authors, and neither IMI nor the European Union or EFPIA is responsible for any use that may be made of the information contained herein. Financial support from the Slovenian Research Agency (grant nos. P1-0208, J1-3030, J1-3031) was gratefully acknowledged. S.R.H. was supported by an iCASE studentship funded by BBSRC and Redx Pharma Plc (BB/J014524/1). Work in A.M.’s lab was supported by an Investigator Award from the Wellcome Trust (110072/Z/15/Z) and by a BBSRC Institute Strategic Programme Grant (BB/P012523/1). The authors thank Diamond Light Source for access to beamlines I03, I04, I04-1, and I24 under proposals MX18565 and MX25108.

Publisher Copyright:
© 2023 American Chemical Society. All rights reserved.

Funding

The research presented in this paper was conducted as part of the ND4BB ENABLE Consortium and has received support from the Innovative Medicines Initiative Joint Undertaking under grant no. 115583, resources of which are comprised of financial contributions from the European Union’s seventh framework program (FP7/2007-2013) and EFPIA companies’ in-kind contribution. The views expressed in this article are the views of the authors, and neither IMI nor the European Union or EFPIA is responsible for any use that may be made of the information contained herein. Financial support from the Slovenian Research Agency (grant nos. P1-0208, J1-3030, J1-3031) was gratefully acknowledged. S.R.H. was supported by an iCASE studentship funded by BBSRC and Redx Pharma Plc (BB/J014524/1). Work in A.M.’s lab was supported by an Investigator Award from the Wellcome Trust (110072/Z/15/Z) and by a BBSRC Institute Strategic Programme Grant (BB/P012523/1). The authors thank Diamond Light Source for access to beamlines I03, I04, I04-1, and I24 under proposals MX18565 and MX25108.

Funders	Funder number
Innovative Medicines Initiative
Seventh Framework Programme	FP7/2007-2013
Javna Agencija za Raziskovalno Dejavnost RS	P1-0208, J1-3030, J1-3031
Wellcome Trust	BB/P012523/1, 110072/Z/15/Z
Biotechnology and Biological Sciences Research Council	BB/J014524/1
Seventh Framework Programme	115583

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10.1021/acs.jmedchem.2c01597

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Cotman, A. E., Durcik, M., Benedetto Tiz, D., Fulgheri, F., Secci, D., Sterle, M., Možina, Š., Skok, Ž., Zidar, N., Zega, A., Ilaš, J., Peterlin Mašič, L., Tomašič, T., Hughes, D., Huseby, D. L., Cao, S., Garoff, L., Berruga Fernández, T., Giachou, P., ... Kikelj, D. (2023). Discovery and Hit-to-Lead Optimization of Benzothiazole Scaffold-Based DNA Gyrase Inhibitors with Potent Activity against Acinetobacter baumannii and Pseudomonas aeruginosa. Journal of medicinal chemistry, 66(2), 1380-1425. https://doi.org/10.1021/acs.jmedchem.2c01597

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

abstract = "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.",

author = "Cotman, {Andrej Emanuel} and Martina Durcik and {Benedetto Tiz}, Davide and Federica Fulgheri and Daniela Secci and Ma{\v s}a Sterle and {\v S}tefan Mo{\v z}ina and {\v Z}iga Skok and Nace Zidar and Anamarija Zega and Janez Ila{\v s} and {Peterlin Ma{\v s}i{\v c}}, Lucija and Tihomir Toma{\v s}i{\v c} and Diarmaid Hughes and Huseby, {Douglas L.} and Sha Cao and Linn{\'e}a Garoff and {Berruga Fern{\'a}ndez}, Tal{\'i}a and Paraskevi Giachou and Lisa Crone and Ivailo Simoff and Richard Svensson and Bryndis Birnir and Korol, {Sergiy V.} and Zhe Jin and Francisca Vicente and Ramos, {Maria C.} and {De La Cruz}, Mercedes and Bj{\"o}rn Glinghammar and Lena Lenhammar and Henderson, {Sara R.} and Mundy, {Julia E.A.} and Anthony Maxwell and Stevenson, {Clare E.M.} and Lawson, {David M.} and Janssen, {Guido V.} and Sterk, {Geert Jan} and Danijel Kikelj",

note = "Funding Information: The research presented in this paper was conducted as part of the ND4BB ENABLE Consortium and has received support from the Innovative Medicines Initiative Joint Undertaking under grant no. 115583, resources of which are comprised of financial contributions from the European Union{\textquoteright}s seventh framework program (FP7/2007-2013) and EFPIA companies{\textquoteright} in-kind contribution. The views expressed in this article are the views of the authors, and neither IMI nor the European Union or EFPIA is responsible for any use that may be made of the information contained herein. Financial support from the Slovenian Research Agency (grant nos. P1-0208, J1-3030, J1-3031) was gratefully acknowledged. S.R.H. was supported by an iCASE studentship funded by BBSRC and Redx Pharma Plc (BB/J014524/1). Work in A.M.{\textquoteright}s lab was supported by an Investigator Award from the Wellcome Trust (110072/Z/15/Z) and by a BBSRC Institute Strategic Programme Grant (BB/P012523/1). The authors thank Diamond Light Source for access to beamlines I03, I04, I04-1, and I24 under proposals MX18565 and MX25108. Publisher Copyright: {\textcopyright} 2023 American Chemical Society. All rights reserved.",

year = "2023",

month = jan,

day = "26",

doi = "10.1021/acs.jmedchem.2c01597",

language = "English",

volume = "66",

pages = "1380--1425",

journal = "Journal of medicinal chemistry",

issn = "0022-2623",

publisher = "American Chemical Society",

number = "2",

}

Cotman, AE, Durcik, M, Benedetto Tiz, D, Fulgheri, F, Secci, D, Sterle, M, Možina, Š, Skok, Ž, Zidar, N, Zega, A, Ilaš, J, Peterlin Mašič, L, Tomašič, T, Hughes, D, Huseby, DL, Cao, S, Garoff, L, Berruga Fernández, T, Giachou, P, Crone, L, Simoff, I, Svensson, R, Birnir, B, Korol, SV, Jin, Z, Vicente, F, Ramos, MC, De La Cruz, M, Glinghammar, B, Lenhammar, L, Henderson, SR, Mundy, JEA, Maxwell, A, Stevenson, CEM, Lawson, DM, Janssen, GV, Sterk, GJ & Kikelj, D 2023, 'Discovery and Hit-to-Lead Optimization of Benzothiazole Scaffold-Based DNA Gyrase Inhibitors with Potent Activity against Acinetobacter baumannii and Pseudomonas aeruginosa', Journal of medicinal chemistry, vol. 66, no. 2, pp. 1380-1425. https://doi.org/10.1021/acs.jmedchem.2c01597

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 et al.
In: Journal of medicinal chemistry, Vol. 66, No. 2, 26.01.2023, p. 1380-1425.

Research output: Contribution to Journal › Article › Academic › peer-review

TY - JOUR

T1 - Discovery and Hit-to-Lead Optimization of Benzothiazole Scaffold-Based DNA Gyrase Inhibitors with Potent Activity against Acinetobacter baumannii and Pseudomonas aeruginosa

AU - Cotman, Andrej Emanuel

AU - Durcik, Martina

AU - Benedetto Tiz, Davide

AU - Fulgheri, Federica

AU - Secci, Daniela

AU - Sterle, Maša

AU - Možina, Štefan

AU - Skok, Žiga

AU - Zidar, Nace

AU - Zega, Anamarija

AU - Ilaš, Janez

AU - Peterlin Mašič, Lucija

AU - Tomašič, Tihomir

AU - Hughes, Diarmaid

AU - Huseby, Douglas L.

AU - Cao, Sha

AU - Garoff, Linnéa

AU - Berruga Fernández, Talía

AU - Giachou, Paraskevi

AU - Crone, Lisa

AU - Simoff, Ivailo

AU - Svensson, Richard

AU - Birnir, Bryndis

AU - Korol, Sergiy V.

AU - Jin, Zhe

AU - Vicente, Francisca

AU - Ramos, Maria C.

AU - De La Cruz, Mercedes

AU - Glinghammar, Björn

AU - Lenhammar, Lena

AU - Henderson, Sara R.

AU - Mundy, Julia E.A.

AU - Maxwell, Anthony

AU - Stevenson, Clare E.M.

AU - Lawson, David M.

AU - Janssen, Guido V.

AU - Sterk, Geert Jan

AU - Kikelj, Danijel

N1 - Funding Information: The research presented in this paper was conducted as part of the ND4BB ENABLE Consortium and has received support from the Innovative Medicines Initiative Joint Undertaking under grant no. 115583, resources of which are comprised of financial contributions from the European Union’s seventh framework program (FP7/2007-2013) and EFPIA companies’ in-kind contribution. The views expressed in this article are the views of the authors, and neither IMI nor the European Union or EFPIA is responsible for any use that may be made of the information contained herein. Financial support from the Slovenian Research Agency (grant nos. P1-0208, J1-3030, J1-3031) was gratefully acknowledged. S.R.H. was supported by an iCASE studentship funded by BBSRC and Redx Pharma Plc (BB/J014524/1). Work in A.M.’s lab was supported by an Investigator Award from the Wellcome Trust (110072/Z/15/Z) and by a BBSRC Institute Strategic Programme Grant (BB/P012523/1). The authors thank Diamond Light Source for access to beamlines I03, I04, I04-1, and I24 under proposals MX18565 and MX25108. Publisher Copyright: © 2023 American Chemical Society. All rights reserved.

PY - 2023/1/26

Y1 - 2023/1/26

N2 - 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.

AB - 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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DO - 10.1021/acs.jmedchem.2c01597

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SN - 0022-2623

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JO - Journal of medicinal chemistry

JF - Journal of medicinal chemistry

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ER -

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

Abstract

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