New Dual Inhibitors of Bacterial Topoisomerases with Broad-Spectrum Antibacterial Activity and In Vivo Efficacy against Vancomycin-Intermediate Staphylococcus aureus

Martina Durcik; Andrej Emanuel Cotman; Žan Toplak; Štefan Možina; Žiga Skok; Petra Eva Szili; Márton Czikkely; Elvin Maharramov; Thu Hien Vu; Maria Vittoria Piras; Nace Zidar; Janez Ilaš; Anamarija Zega; Jurij Trontelj; Luis A. Pardo; Diarmaid Hughes; Douglas Huseby; Tália Berruga-Fernández; Sha Cao; Ivailo Simoff; Richard Svensson; Sergiy V. Korol; Zhe Jin; Francisca Vicente; Maria C. Ramos; Julia E.A. Mundy; Anthony Maxwell; Clare E.M. Stevenson; David M. Lawson; Björn Glinghammar; Eva Sjöström; Martin Bohlin; Joanna Oreskär; Sofie Alvér; Guido V. Janssen; Geert Jan Sterk; Danijel Kikelj; Csaba Pal; Tihomir Tomašič; Lucija Peterlin Mašič

doi:10.1021/acs.jmedchem.2c01905

New Dual Inhibitors of Bacterial Topoisomerases with Broad-Spectrum Antibacterial Activity and In Vivo Efficacy against Vancomycin-Intermediate Staphylococcus aureus

Martina Durcik, Andrej Emanuel Cotman, Žan Toplak, Štefan Možina, Žiga Skok, Petra Eva Szili, Márton Czikkely, Elvin Maharramov, Thu Hien Vu, Maria Vittoria Piras, Nace Zidar, Janez Ilaš, Anamarija Zega, Jurij Trontelj, Luis A. Pardo, Diarmaid Hughes, Douglas Huseby, Tália Berruga-Fernández, Sha Cao, Ivailo SimoffRichard Svensson, Sergiy V. Korol, Zhe Jin, Francisca Vicente, Maria C. Ramos, Julia E.A. Mundy, Anthony Maxwell, Clare E.M. Stevenson, David M. Lawson, Björn Glinghammar, Eva Sjöström, Martin Bohlin, Joanna Oreskär, Sofie Alvér, Guido V. Janssen, Geert Jan Sterk, Danijel Kikelj, Csaba Pal, Tihomir Tomašič^*, Lucija Peterlin Mašič^*

^*Corresponding author for this work

AIMMS

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

Abstract

A new series of dual low nanomolar benzothiazole inhibitors of bacterial DNA gyrase and topoisomerase IV were developed. The resulting compounds show excellent broad-spectrum antibacterial activities against Gram-positive Enterococcus faecalis, Enterococcus faecium and multidrug resistant (MDR) Staphylococcus aureus strains [best compound minimal inhibitory concentrations (MICs): range, <0.03125-0.25 μg/mL] and against the Gram-negatives Acinetobacter baumannii and Klebsiella pneumoniae (best compound MICs: range, 1-4 μg/mL). Lead compound 7a was identified with favorable solubility and plasma protein binding, good metabolic stability, selectivity for bacterial topoisomerases, and no toxicity issues. The crystal structure of 7a in complex with Pseudomonas aeruginosa GyrB24 revealed its binding mode at the ATP-binding site. Expanded profiling of 7a and 7h showed potent antibacterial activity against over 100 MDR and non-MDR strains of A. baumannii and several other Gram-positive and Gram-negative strains. Ultimately, in vivo efficacy of 7a in a mouse model of vancomycin-intermediate S. aureus thigh infection was also demonstrated.

Original language	English
Pages (from-to)	3968-3994
Number of pages	27
Journal	Journal of medicinal chemistry
Volume	66
Issue number	6
Early online date	6 Mar 2023
DOIs	https://doi.org/10.1021/acs.jmedchem.2c01905
Publication status	Published - 23 Mar 2023

Bibliographical note

Funding Information:
The study was funded by the Slovenian Research Agency (grant no. P1-0208, J1-3030, J1-3031, and BI-HU/19-20-008). Part of 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 comprising financial contributions from the European Union’s seventh framework program (FP7/2007–2013) and EFPIA companies’ in-kind contribution. S.R.H. was supported by an iCASE studentship funded by BBSRC and Redx Pharma Plc (BB/J014524/1). Work in A.M. laboratory is supported by an Investigator Award from the Wellcome Trust (110072/Z/15/Z) and by a BBSRC Institute Strategic Programme Grant (BB/P012523/1). We thank Diamond Light Source for access to beamline I04 under proposal MX25108. Work in C.P. laboratory is supported by the following research grants: the National Research Development and Innovation Office “Élvonal” Programme KKP 126506 (C.P.), the ELKH Lendület Programme LP-2017–10/2020 (C.P.), the National Laboratory of Biotechnology Grant NKFIH-871-3/2020 (C.P.), the National Laboratory of Biotechnology Grant 2022-2.1.1-NL-2022-00008 (C.P.), the European Research Council H2020-ERC-2014-CoG 648364- Resistance Evolution (C.P.), the ÚNKP-22-4 New National Excellence Program of the Ministry for Culture and Innovation from the Source of the National Research, Development and Innovation Fund (P.E.S.), the ÚNKP-22-4 New National Excellence Program of the Ministry for Culture and Innovation from the Source of the National Research, the Development and Innovation Fund (P.E.S.), the National Academy of Scientist Education Program of the National Biomedical Foundation under the sponsorship of the Hungarian Ministry of Culture and Innovation (M.C.), and the ÚNKP-22-2 New National Excellence Program of the Ministry for Culture and Innovation from the Source of the National Research, Development and Innovation Fund (M.C.). The authors thank Dora Bokor for proofreading the manuscript.

Funding Information:
The study was funded by the Slovenian Research Agency (grant no. P1-0208, J1-3030, J1-3031, and BI-HU/19-20-008). Part of 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 comprising financial contributions from the European Union’s seventh framework program (FP7/2007-2013) and EFPIA companies’ in-kind contribution. S.R.H. was supported by an iCASE studentship funded by BBSRC and Redx Pharma Plc (BB/J014524/1). Work in A.M. laboratory is supported by an Investigator Award from the Wellcome Trust (110072/Z/15/Z) and by a BBSRC Institute Strategic Programme Grant (BB/P012523/1). We thank Diamond Light Source for access to beamline I04 under proposal MX25108. Work in C.P. laboratory is supported by the following research grants: the National Research Development and Innovation Office “Élvonal” Programme KKP 126506 (C.P.), the ELKH Lendület Programme LP-2017-10/2020 (C.P.), the National Laboratory of Biotechnology Grant NKFIH-871-3/2020 (C.P.), the National Laboratory of Biotechnology Grant 2022-2.1.1-NL-2022-00008 (C.P.), the European Research Council H2020-ERC-2014-CoG 648364- Resistance Evolution (C.P.), the ÚNKP-22-4 New National Excellence Program of the Ministry for Culture and Innovation from the Source of the National Research, Development and Innovation Fund (P.E.S.), the ÚNKP-22-4 New National Excellence Program of the Ministry for Culture and Innovation from the Source of the National Research, the Development and Innovation Fund (P.E.S.), the National Academy of Scientist Education Program of the National Biomedical Foundation under the sponsorship of the Hungarian Ministry of Culture and Innovation (M.C.), and the ÚNKP-22-2 New National Excellence Program of the Ministry for Culture and Innovation from the Source of the National Research, Development and Innovation Fund (M.C.). The authors thank Dora Bokor for proofreading the manuscript.

Publisher Copyright:
© 2023 The Authors. Published by American Chemical Society.

Funding

The study was funded by the Slovenian Research Agency (grant no. P1-0208, J1-3030, J1-3031, and BI-HU/19-20-008). Part of 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 comprising financial contributions from the European Union’s seventh framework program (FP7/2007–2013) and EFPIA companies’ in-kind contribution. S.R.H. was supported by an iCASE studentship funded by BBSRC and Redx Pharma Plc (BB/J014524/1). Work in A.M. laboratory is supported by an Investigator Award from the Wellcome Trust (110072/Z/15/Z) and by a BBSRC Institute Strategic Programme Grant (BB/P012523/1). We thank Diamond Light Source for access to beamline I04 under proposal MX25108. Work in C.P. laboratory is supported by the following research grants: the National Research Development and Innovation Office “Élvonal” Programme KKP 126506 (C.P.), the ELKH Lendület Programme LP-2017–10/2020 (C.P.), the National Laboratory of Biotechnology Grant NKFIH-871-3/2020 (C.P.), the National Laboratory of Biotechnology Grant 2022-2.1.1-NL-2022-00008 (C.P.), the European Research Council H2020-ERC-2014-CoG 648364- Resistance Evolution (C.P.), the ÚNKP-22-4 New National Excellence Program of the Ministry for Culture and Innovation from the Source of the National Research, Development and Innovation Fund (P.E.S.), the ÚNKP-22-4 New National Excellence Program of the Ministry for Culture and Innovation from the Source of the National Research, the Development and Innovation Fund (P.E.S.), the National Academy of Scientist Education Program of the National Biomedical Foundation under the sponsorship of the Hungarian Ministry of Culture and Innovation (M.C.), and the ÚNKP-22-2 New National Excellence Program of the Ministry for Culture and Innovation from the Source of the National Research, Development and Innovation Fund (M.C.). The authors thank Dora Bokor for proofreading the manuscript. The study was funded by the Slovenian Research Agency (grant no. P1-0208, J1-3030, J1-3031, and BI-HU/19-20-008). Part of 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 comprising financial contributions from the European Union’s seventh framework program (FP7/2007-2013) and EFPIA companies’ in-kind contribution. S.R.H. was supported by an iCASE studentship funded by BBSRC and Redx Pharma Plc (BB/J014524/1). Work in A.M. laboratory is supported by an Investigator Award from the Wellcome Trust (110072/Z/15/Z) and by a BBSRC Institute Strategic Programme Grant (BB/P012523/1). We thank Diamond Light Source for access to beamline I04 under proposal MX25108. Work in C.P. laboratory is supported by the following research grants: the National Research Development and Innovation Office “Élvonal” Programme KKP 126506 (C.P.), the ELKH Lendület Programme LP-2017-10/2020 (C.P.), the National Laboratory of Biotechnology Grant NKFIH-871-3/2020 (C.P.), the National Laboratory of Biotechnology Grant 2022-2.1.1-NL-2022-00008 (C.P.), the European Research Council H2020-ERC-2014-CoG 648364- Resistance Evolution (C.P.), the ÚNKP-22-4 New National Excellence Program of the Ministry for Culture and Innovation from the Source of the National Research, Development and Innovation Fund (P.E.S.), the ÚNKP-22-4 New National Excellence Program of the Ministry for Culture and Innovation from the Source of the National Research, the Development and Innovation Fund (P.E.S.), the National Academy of Scientist Education Program of the National Biomedical Foundation under the sponsorship of the Hungarian Ministry of Culture and Innovation (M.C.), and the ÚNKP-22-2 New National Excellence Program of the Ministry for Culture and Innovation from the Source of the National Research, Development and Innovation Fund (M.C.). The authors thank Dora Bokor for proofreading the manuscript.

Funders	Funder number
European Federation of Pharmaceutical Industries and Associations
Hungarian Ministry of Culture and Innovation
Horizon 2020 Framework Programme
National Academy of Scientist Education Program of the National Biomedical Foundation
Development and Innovation Fund
Ministry for Culture and Innovation
Nemzeti Kutatási, Fejlesztési és Innovaciós Alap
European Research Council
Innovative Medicines Initiative
Dora Bokor
UK Research and Innovation
Biotechnology and Biological Sciences Research Council	BBS/E/J/000PR9791, BB/J014524/1
Nemzeti Kutatási Fejlesztési és Innovációs Hivatal	LP-2017-10/2020, KKP 126506
Seventh Framework Programme	FP7/2007–2013
Wellcome Trust	BB/P012523/1, MX25108, 110072/Z/15/Z, 110072
Seventh Framework Programme	115583, 648364
National Laboratory of Biotechnology	NKFIH-871-3/2020, 2022-2.1.1-NL-2022-00008
Javna Agencija za Raziskovalno Dejavnost RS	P1-0208, BI-HU/19-20-008, J1-3030, J1-3031

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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Cite this

Durcik, M., Cotman, A. E., Toplak, Ž., Možina, Š., Skok, Ž., Szili, P. E., Czikkely, M., Maharramov, E., Vu, T. H., Piras, M. V., Zidar, N., Ilaš, J., Zega, A., Trontelj, J., Pardo, L. A., Hughes, D., Huseby, D., Berruga-Fernández, T., Cao, S., ... Peterlin Mašič, L. (2023). New Dual Inhibitors of Bacterial Topoisomerases with Broad-Spectrum Antibacterial Activity and In Vivo Efficacy against Vancomycin-Intermediate Staphylococcus aureus. Journal of medicinal chemistry, 66(6), 3968-3994. https://doi.org/10.1021/acs.jmedchem.2c01905

@article{1a32718a5ca0498a92134058273807f4,

title = "New Dual Inhibitors of Bacterial Topoisomerases with Broad-Spectrum Antibacterial Activity and In Vivo Efficacy against Vancomycin-Intermediate Staphylococcus aureus",

abstract = "A new series of dual low nanomolar benzothiazole inhibitors of bacterial DNA gyrase and topoisomerase IV were developed. The resulting compounds show excellent broad-spectrum antibacterial activities against Gram-positive Enterococcus faecalis, Enterococcus faecium and multidrug resistant (MDR) Staphylococcus aureus strains [best compound minimal inhibitory concentrations (MICs): range, <0.03125-0.25 μg/mL] and against the Gram-negatives Acinetobacter baumannii and Klebsiella pneumoniae (best compound MICs: range, 1-4 μg/mL). Lead compound 7a was identified with favorable solubility and plasma protein binding, good metabolic stability, selectivity for bacterial topoisomerases, and no toxicity issues. The crystal structure of 7a in complex with Pseudomonas aeruginosa GyrB24 revealed its binding mode at the ATP-binding site. Expanded profiling of 7a and 7h showed potent antibacterial activity against over 100 MDR and non-MDR strains of A. baumannii and several other Gram-positive and Gram-negative strains. Ultimately, in vivo efficacy of 7a in a mouse model of vancomycin-intermediate S. aureus thigh infection was also demonstrated.",

author = "Martina Durcik and Cotman, \{Andrej Emanuel\} and {\v Z}an Toplak and {\v S}tefan Mo{\v z}ina and {\v Z}iga Skok and Szili, \{Petra Eva\} and M{\'a}rton Czikkely and Elvin Maharramov and Vu, \{Thu Hien\} and Piras, \{Maria Vittoria\} and Nace Zidar and Janez Ila{\v s} and Anamarija Zega and Jurij Trontelj and Pardo, \{Luis A.\} and Diarmaid Hughes and Douglas Huseby and T{\'a}lia Berruga-Fern{\'a}ndez and Sha Cao and Ivailo Simoff and Richard Svensson and Korol, \{Sergiy V.\} and Zhe Jin and Francisca Vicente and Ramos, \{Maria C.\} and Mundy, \{Julia E.A.\} and Anthony Maxwell and Stevenson, \{Clare E.M.\} and Lawson, \{David M.\} and Bj{\"o}rn Glinghammar and Eva Sj{\"o}str{\"o}m and Martin Bohlin and Joanna Oresk{\"a}r and Sofie Alv{\'e}r and Janssen, \{Guido V.\} and Sterk, \{Geert Jan\} and Danijel Kikelj and Csaba Pal and Tihomir Toma{\v s}i{\v c} and \{Peterlin Ma{\v s}i{\v c}\}, Lucija",

note = "Funding Information: The study was funded by the Slovenian Research Agency (grant no. P1-0208, J1-3030, J1-3031, and BI-HU/19-20-008). Part of 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 comprising financial contributions from the European Union{\textquoteright}s seventh framework program (FP7/2007–2013) and EFPIA companies{\textquoteright} in-kind contribution. S.R.H. was supported by an iCASE studentship funded by BBSRC and Redx Pharma Plc (BB/J014524/1). Work in A.M. laboratory is supported by an Investigator Award from the Wellcome Trust (110072/Z/15/Z) and by a BBSRC Institute Strategic Programme Grant (BB/P012523/1). We thank Diamond Light Source for access to beamline I04 under proposal MX25108. Work in C.P. laboratory is supported by the following research grants: the National Research Development and Innovation Office “{\'E}lvonal” Programme KKP 126506 (C.P.), the ELKH Lend{\"u}let Programme LP-2017–10/2020 (C.P.), the National Laboratory of Biotechnology Grant NKFIH-871-3/2020 (C.P.), the National Laboratory of Biotechnology Grant 2022-2.1.1-NL-2022-00008 (C.P.), the European Research Council H2020-ERC-2014-CoG 648364- Resistance Evolution (C.P.), the {\'U}NKP-22-4 New National Excellence Program of the Ministry for Culture and Innovation from the Source of the National Research, Development and Innovation Fund (P.E.S.), the {\'U}NKP-22-4 New National Excellence Program of the Ministry for Culture and Innovation from the Source of the National Research, the Development and Innovation Fund (P.E.S.), the National Academy of Scientist Education Program of the National Biomedical Foundation under the sponsorship of the Hungarian Ministry of Culture and Innovation (M.C.), and the {\'U}NKP-22-2 New National Excellence Program of the Ministry for Culture and Innovation from the Source of the National Research, Development and Innovation Fund (M.C.). The authors thank Dora Bokor for proofreading the manuscript. Funding Information: The study was funded by the Slovenian Research Agency (grant no. P1-0208, J1-3030, J1-3031, and BI-HU/19-20-008). Part of 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 comprising financial contributions from the European Union{\textquoteright}s seventh framework program (FP7/2007-2013) and EFPIA companies{\textquoteright} in-kind contribution. S.R.H. was supported by an iCASE studentship funded by BBSRC and Redx Pharma Plc (BB/J014524/1). Work in A.M. laboratory is supported by an Investigator Award from the Wellcome Trust (110072/Z/15/Z) and by a BBSRC Institute Strategic Programme Grant (BB/P012523/1). We thank Diamond Light Source for access to beamline I04 under proposal MX25108. Work in C.P. laboratory is supported by the following research grants: the National Research Development and Innovation Office “{\'E}lvonal” Programme KKP 126506 (C.P.), the ELKH Lend{\"u}let Programme LP-2017-10/2020 (C.P.), the National Laboratory of Biotechnology Grant NKFIH-871-3/2020 (C.P.), the National Laboratory of Biotechnology Grant 2022-2.1.1-NL-2022-00008 (C.P.), the European Research Council H2020-ERC-2014-CoG 648364- Resistance Evolution (C.P.), the {\'U}NKP-22-4 New National Excellence Program of the Ministry for Culture and Innovation from the Source of the National Research, Development and Innovation Fund (P.E.S.), the {\'U}NKP-22-4 New National Excellence Program of the Ministry for Culture and Innovation from the Source of the National Research, the Development and Innovation Fund (P.E.S.), the National Academy of Scientist Education Program of the National Biomedical Foundation under the sponsorship of the Hungarian Ministry of Culture and Innovation (M.C.), and the {\'U}NKP-22-2 New National Excellence Program of the Ministry for Culture and Innovation from the Source of the National Research, Development and Innovation Fund (M.C.). The authors thank Dora Bokor for proofreading the manuscript. Publisher Copyright: {\textcopyright} 2023 The Authors. Published by American Chemical Society.",

year = "2023",

month = mar,

day = "23",

doi = "10.1021/acs.jmedchem.2c01905",

language = "English",

volume = "66",

pages = "3968--3994",

journal = "Journal of medicinal chemistry",

issn = "0022-2623",

publisher = "American Chemical Society",

number = "6",

}

Durcik, M, Cotman, AE, Toplak, Ž, Možina, Š, Skok, Ž, Szili, PE, Czikkely, M, Maharramov, E, Vu, TH, Piras, MV, Zidar, N, Ilaš, J, Zega, A, Trontelj, J, Pardo, LA, Hughes, D, Huseby, D, Berruga-Fernández, T, Cao, S, Simoff, I, Svensson, R, Korol, SV, Jin, Z, Vicente, F, Ramos, MC, Mundy, JEA, Maxwell, A, Stevenson, CEM, Lawson, DM, Glinghammar, B, Sjöström, E, Bohlin, M, Oreskär, J, Alvér, S, Janssen, GV, Sterk, GJ, Kikelj, D, Pal, C, Tomašič, T & Peterlin Mašič, L 2023, 'New Dual Inhibitors of Bacterial Topoisomerases with Broad-Spectrum Antibacterial Activity and In Vivo Efficacy against Vancomycin-Intermediate Staphylococcus aureus', Journal of medicinal chemistry, vol. 66, no. 6, pp. 3968-3994. https://doi.org/10.1021/acs.jmedchem.2c01905

New Dual Inhibitors of Bacterial Topoisomerases with Broad-Spectrum Antibacterial Activity and In Vivo Efficacy against Vancomycin-Intermediate Staphylococcus aureus. / Durcik, Martina; Cotman, Andrej Emanuel; Toplak, Žan et al.
In: Journal of medicinal chemistry, Vol. 66, No. 6, 23.03.2023, p. 3968-3994.

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

TY - JOUR

T1 - New Dual Inhibitors of Bacterial Topoisomerases with Broad-Spectrum Antibacterial Activity and In Vivo Efficacy against Vancomycin-Intermediate Staphylococcus aureus

AU - Durcik, Martina

AU - Cotman, Andrej Emanuel

AU - Toplak, Žan

AU - Možina, Štefan

AU - Skok, Žiga

AU - Szili, Petra Eva

AU - Czikkely, Márton

AU - Maharramov, Elvin

AU - Vu, Thu Hien

AU - Piras, Maria Vittoria

AU - Zidar, Nace

AU - Ilaš, Janez

AU - Zega, Anamarija

AU - Trontelj, Jurij

AU - Pardo, Luis A.

AU - Hughes, Diarmaid

AU - Huseby, Douglas

AU - Berruga-Fernández, Tália

AU - Cao, Sha

AU - Simoff, Ivailo

AU - Svensson, Richard

AU - Korol, Sergiy V.

AU - Jin, Zhe

AU - Vicente, Francisca

AU - Ramos, Maria C.

AU - Mundy, Julia E.A.

AU - Maxwell, Anthony

AU - Stevenson, Clare E.M.

AU - Lawson, David M.

AU - Glinghammar, Björn

AU - Sjöström, Eva

AU - Bohlin, Martin

AU - Oreskär, Joanna

AU - Alvér, Sofie

AU - Janssen, Guido V.

AU - Sterk, Geert Jan

AU - Kikelj, Danijel

AU - Pal, Csaba

AU - Tomašič, Tihomir

AU - Peterlin Mašič, Lucija

N1 - Funding Information: The study was funded by the Slovenian Research Agency (grant no. P1-0208, J1-3030, J1-3031, and BI-HU/19-20-008). Part of 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 comprising financial contributions from the European Union’s seventh framework program (FP7/2007–2013) and EFPIA companies’ in-kind contribution. S.R.H. was supported by an iCASE studentship funded by BBSRC and Redx Pharma Plc (BB/J014524/1). Work in A.M. laboratory is supported by an Investigator Award from the Wellcome Trust (110072/Z/15/Z) and by a BBSRC Institute Strategic Programme Grant (BB/P012523/1). We thank Diamond Light Source for access to beamline I04 under proposal MX25108. Work in C.P. laboratory is supported by the following research grants: the National Research Development and Innovation Office “Élvonal” Programme KKP 126506 (C.P.), the ELKH Lendület Programme LP-2017–10/2020 (C.P.), the National Laboratory of Biotechnology Grant NKFIH-871-3/2020 (C.P.), the National Laboratory of Biotechnology Grant 2022-2.1.1-NL-2022-00008 (C.P.), the European Research Council H2020-ERC-2014-CoG 648364- Resistance Evolution (C.P.), the ÚNKP-22-4 New National Excellence Program of the Ministry for Culture and Innovation from the Source of the National Research, Development and Innovation Fund (P.E.S.), the ÚNKP-22-4 New National Excellence Program of the Ministry for Culture and Innovation from the Source of the National Research, the Development and Innovation Fund (P.E.S.), the National Academy of Scientist Education Program of the National Biomedical Foundation under the sponsorship of the Hungarian Ministry of Culture and Innovation (M.C.), and the ÚNKP-22-2 New National Excellence Program of the Ministry for Culture and Innovation from the Source of the National Research, Development and Innovation Fund (M.C.). The authors thank Dora Bokor for proofreading the manuscript. Funding Information: The study was funded by the Slovenian Research Agency (grant no. P1-0208, J1-3030, J1-3031, and BI-HU/19-20-008). Part of 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 comprising financial contributions from the European Union’s seventh framework program (FP7/2007-2013) and EFPIA companies’ in-kind contribution. S.R.H. was supported by an iCASE studentship funded by BBSRC and Redx Pharma Plc (BB/J014524/1). Work in A.M. laboratory is supported by an Investigator Award from the Wellcome Trust (110072/Z/15/Z) and by a BBSRC Institute Strategic Programme Grant (BB/P012523/1). We thank Diamond Light Source for access to beamline I04 under proposal MX25108. Work in C.P. laboratory is supported by the following research grants: the National Research Development and Innovation Office “Élvonal” Programme KKP 126506 (C.P.), the ELKH Lendület Programme LP-2017-10/2020 (C.P.), the National Laboratory of Biotechnology Grant NKFIH-871-3/2020 (C.P.), the National Laboratory of Biotechnology Grant 2022-2.1.1-NL-2022-00008 (C.P.), the European Research Council H2020-ERC-2014-CoG 648364- Resistance Evolution (C.P.), the ÚNKP-22-4 New National Excellence Program of the Ministry for Culture and Innovation from the Source of the National Research, Development and Innovation Fund (P.E.S.), the ÚNKP-22-4 New National Excellence Program of the Ministry for Culture and Innovation from the Source of the National Research, the Development and Innovation Fund (P.E.S.), the National Academy of Scientist Education Program of the National Biomedical Foundation under the sponsorship of the Hungarian Ministry of Culture and Innovation (M.C.), and the ÚNKP-22-2 New National Excellence Program of the Ministry for Culture and Innovation from the Source of the National Research, Development and Innovation Fund (M.C.). The authors thank Dora Bokor for proofreading the manuscript. Publisher Copyright: © 2023 The Authors. Published by American Chemical Society.

PY - 2023/3/23

Y1 - 2023/3/23

N2 - A new series of dual low nanomolar benzothiazole inhibitors of bacterial DNA gyrase and topoisomerase IV were developed. The resulting compounds show excellent broad-spectrum antibacterial activities against Gram-positive Enterococcus faecalis, Enterococcus faecium and multidrug resistant (MDR) Staphylococcus aureus strains [best compound minimal inhibitory concentrations (MICs): range, <0.03125-0.25 μg/mL] and against the Gram-negatives Acinetobacter baumannii and Klebsiella pneumoniae (best compound MICs: range, 1-4 μg/mL). Lead compound 7a was identified with favorable solubility and plasma protein binding, good metabolic stability, selectivity for bacterial topoisomerases, and no toxicity issues. The crystal structure of 7a in complex with Pseudomonas aeruginosa GyrB24 revealed its binding mode at the ATP-binding site. Expanded profiling of 7a and 7h showed potent antibacterial activity against over 100 MDR and non-MDR strains of A. baumannii and several other Gram-positive and Gram-negative strains. Ultimately, in vivo efficacy of 7a in a mouse model of vancomycin-intermediate S. aureus thigh infection was also demonstrated.

AB - A new series of dual low nanomolar benzothiazole inhibitors of bacterial DNA gyrase and topoisomerase IV were developed. The resulting compounds show excellent broad-spectrum antibacterial activities against Gram-positive Enterococcus faecalis, Enterococcus faecium and multidrug resistant (MDR) Staphylococcus aureus strains [best compound minimal inhibitory concentrations (MICs): range, <0.03125-0.25 μg/mL] and against the Gram-negatives Acinetobacter baumannii and Klebsiella pneumoniae (best compound MICs: range, 1-4 μg/mL). Lead compound 7a was identified with favorable solubility and plasma protein binding, good metabolic stability, selectivity for bacterial topoisomerases, and no toxicity issues. The crystal structure of 7a in complex with Pseudomonas aeruginosa GyrB24 revealed its binding mode at the ATP-binding site. Expanded profiling of 7a and 7h showed potent antibacterial activity against over 100 MDR and non-MDR strains of A. baumannii and several other Gram-positive and Gram-negative strains. Ultimately, in vivo efficacy of 7a in a mouse model of vancomycin-intermediate S. aureus thigh infection was also demonstrated.

UR - https://www.scopus.com/pages/publications/85149718595

UR - https://www.scopus.com/inward/citedby.url?scp=85149718595&partnerID=8YFLogxK

U2 - 10.1021/acs.jmedchem.2c01905

DO - 10.1021/acs.jmedchem.2c01905

M3 - Article

C2 - 36877255

AN - SCOPUS:85149718595

SN - 0022-2623

VL - 66

SP - 3968

EP - 3994

JO - Journal of medicinal chemistry

JF - Journal of medicinal chemistry

IS - 6

ER -

New Dual Inhibitors of Bacterial Topoisomerases with Broad-Spectrum Antibacterial Activity and In Vivo Efficacy against Vancomycin-Intermediate Staphylococcus aureus

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UN SDGs

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