Topoisomerase Inhibitors Addressing Fluoroquinolone Resistance in Gram-Negative Bacteria

Colin K. Skepper; Duncan Armstrong; Carl J. Balibar; Daniel Bauer; Cornelia Bellamacina; Bret M. Benton; Dirksen Bussiere; Gianfranco De Pascale; Javier De Vicente; Charles R. Dean; Bhavesh Dhumale; L. Mark Fisher; John Fuller; Mangesh Fulsunder; Lauren M. Holder; Cheng Hu; Bhavin Kantariya; Guillaume Lapointe; Jennifer A. Leeds; Xiaolin Li; Peichao Lu; Anatoli Lvov; Sylvia Ma; Shravanthi Madhavan; Swapnil Malekar; David Mckenney; Wosenu Mergo; Louis Metzger; Heinz E. Moser; Daniel Mutnick; Jonas Noeske; Colin Osborne; Ashish Patel; Darshit Patel; Tushar Patel; Krunal Prajapati; Katherine R. Prosen; Folkert Reck; Daryl L. Richie; Alice Rico; Mark R. Sanderson; Shailesh Satasia; William S. Sawyer; Jogitha Selvarajah; Nirav Shah; Kartik Shanghavi; Wei Shu; Katherine V. Thompson; Dennis A. Veselkov; Sarah L. Williams; Yongjin Xu; Qin   Yue; Richard  Zang; Bo  Zho; Alexey  Rivkin

doi:10.1021/acs.jmedchem.0c00347

Topoisomerase Inhibitors Addressing Fluoroquinolone Resistance in Gram-Negative Bacteria

Colin K. Skepper, Duncan Armstrong, Carl J. Balibar, Daniel Bauer, Cornelia Bellamacina, Bret M. Benton, Dirksen Bussiere, Gianfranco De Pascale, Javier De Vicente, Charles R. Dean, Bhavesh Dhumale, L. Mark Fisher, John Fuller, Mangesh Fulsunder, Lauren M. Holder, Cheng Hu, Bhavin Kantariya, Guillaume Lapointe, Jennifer A. Leeds, Xiaolin LiPeichao Lu, Anatoli Lvov, Sylvia Ma, Shravanthi Madhavan, Swapnil Malekar, David Mckenney, Wosenu Mergo, Louis Metzger, Heinz E. Moser, Daniel Mutnick, Jonas Noeske, Colin Osborne, Ashish Patel, Darshit Patel, Tushar Patel, Krunal Prajapati, Katherine R. Prosen, Folkert Reck, Daryl L. Richie, Alice Rico, Mark R. Sanderson, Shailesh Satasia, William S. Sawyer, Jogitha Selvarajah, Nirav Shah, Kartik Shanghavi, Wei Shu, Katherine V. Thompson, Dennis A. Veselkov, Sarah L. Williams, Yongjin Xu, Qin Yue, Richard Zang, Bo Zho, Alexey Rivkin

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Abstract

Since their discovery over 5 decades ago, quinolone antibiotics have found enormous success as broad spectrum agents that exert their activity through dual inhibition of bacterial DNA gyrase and topoisomerase IV. Increasing rates of resistance, driven largely by target-based mutations in the GyrA/ParC quinolone resistance determining region, have eroded the utility and threaten the future use of this vital class of antibiotics. Herein we describe the discovery and optimization of a series of 4-(aminomethyl)quinolin-2(1H)-ones, exemplified by 34, that inhibit bacterial DNA gyrase and topoisomerase IV and display potent activity against ciprofloxacin-resistant Gram-negative pathogens. X-ray crystallography reveals that 34 occupies the classical quinolone binding site in the topoisomerase IV-DNA cleavage complex but does not form significant contacts with residues in the quinolone resistance determining region.

Original language	English
Pages (from-to)	7773-7816
Number of pages	44
Journal	Journal of Medicinal Chemistry
Volume	63
Issue number	14
Early online date	7 Jul 2020
DOIs	https://doi.org/10.1021/acs.jmedchem.0c00347
Publication status	Published - 23 Jul 2020

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Topoisomerase Inhibitors Addressing Fluoroquinolone_SKEPPER_Acc16Jun2020E[ub7Jul2020_GREEN AAMAccepted author manuscript, 7.21 MB

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Skepper, C. K., Armstrong, D., Balibar, C. J., Bauer, D., Bellamacina, C., Benton, B. M., Bussiere, D., De Pascale, G., De Vicente, J., Dean, C. R., Dhumale, B., Fisher, L. M., Fuller, J., Fulsunder, M., Holder, L. M., Hu, C., Kantariya, B., Lapointe, G., Leeds, J. A., ... Rivkin, A. (2020). Topoisomerase Inhibitors Addressing Fluoroquinolone Resistance in Gram-Negative Bacteria. Journal of Medicinal Chemistry, 63(14), 7773-7816. https://doi.org/10.1021/acs.jmedchem.0c00347

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title = "Topoisomerase Inhibitors Addressing Fluoroquinolone Resistance in Gram-Negative Bacteria",

abstract = "Since their discovery over 5 decades ago, quinolone antibiotics have found enormous success as broad spectrum agents that exert their activity through dual inhibition of bacterial DNA gyrase and topoisomerase IV. Increasing rates of resistance, driven largely by target-based mutations in the GyrA/ParC quinolone resistance determining region, have eroded the utility and threaten the future use of this vital class of antibiotics. Herein we describe the discovery and optimization of a series of 4-(aminomethyl)quinolin-2(1H)-ones, exemplified by 34, that inhibit bacterial DNA gyrase and topoisomerase IV and display potent activity against ciprofloxacin-resistant Gram-negative pathogens. X-ray crystallography reveals that 34 occupies the classical quinolone binding site in the topoisomerase IV-DNA cleavage complex but does not form significant contacts with residues in the quinolone resistance determining region.",

author = "Skepper, {Colin K.} and Duncan Armstrong and Balibar, {Carl J.} and Daniel Bauer and Cornelia Bellamacina and Benton, {Bret M.} and Dirksen Bussiere and {De Pascale}, Gianfranco and {De Vicente}, Javier and Dean, {Charles R.} and Bhavesh Dhumale and Fisher, {L. Mark} and John Fuller and Mangesh Fulsunder and Holder, {Lauren M.} and Cheng Hu and Bhavin Kantariya and Guillaume Lapointe and Leeds, {Jennifer A.} and Xiaolin Li and Peichao Lu and Anatoli Lvov and Sylvia Ma and Shravanthi Madhavan and Swapnil Malekar and David Mckenney and Wosenu Mergo and Louis Metzger and Moser, {Heinz E.} and Daniel Mutnick and Jonas Noeske and Colin Osborne and Ashish Patel and Darshit Patel and Tushar Patel and Krunal Prajapati and Prosen, {Katherine R.} and Folkert Reck and Richie, {Daryl L.} and Alice Rico and Sanderson, {Mark R.} and Shailesh Satasia and Sawyer, {William S.} and Jogitha Selvarajah and Nirav Shah and Kartik Shanghavi and Wei Shu and Thompson, {Katherine V.} and Veselkov, {Dennis A.} and Williams, {Sarah L.} and Yongjin Xu and Qin Yue and Richard Zang and Bo Zho and Alexey Rivkin",

year = "2020",

month = jul,

day = "23",

doi = "10.1021/acs.jmedchem.0c00347",

language = "English",

volume = "63",

pages = "7773--7816",

journal = "Journal of Medicinal Chemistry",

issn = "0022-2623",

publisher = "American Chemical Society",

number = "14",

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Skepper, CK, Armstrong, D, Balibar, CJ, Bauer, D, Bellamacina, C, Benton, BM, Bussiere, D, De Pascale, G, De Vicente, J, Dean, CR, Dhumale, B, Fisher, LM, Fuller, J, Fulsunder, M, Holder, LM, Hu, C, Kantariya, B, Lapointe, G, Leeds, JA, Li, X, Lu, P, Lvov, A, Ma, S, Madhavan, S, Malekar, S, Mckenney, D, Mergo, W, Metzger, L, Moser, HE, Mutnick, D, Noeske, J, Osborne, C, Patel, A, Patel, D, Patel, T, Prajapati, K, Prosen, KR, Reck, F, Richie, DL, Rico, A, Sanderson, MR, Satasia, S, Sawyer, WS, Selvarajah, J, Shah, N, Shanghavi, K, Shu, W, Thompson, KV, Veselkov, DA, Williams, SL, Xu, Y, Yue, Q, Zang, R, Zho, B & Rivkin, A 2020, 'Topoisomerase Inhibitors Addressing Fluoroquinolone Resistance in Gram-Negative Bacteria', Journal of Medicinal Chemistry, vol. 63, no. 14, pp. 7773-7816. https://doi.org/10.1021/acs.jmedchem.0c00347

TY - JOUR

T1 - Topoisomerase Inhibitors Addressing Fluoroquinolone Resistance in Gram-Negative Bacteria

AU - Skepper, Colin K.

AU - Armstrong, Duncan

AU - Balibar, Carl J.

AU - Bauer, Daniel

AU - Bellamacina, Cornelia

AU - Benton, Bret M.

AU - Bussiere, Dirksen

AU - De Pascale, Gianfranco

AU - De Vicente, Javier

AU - Dean, Charles R.

AU - Dhumale, Bhavesh

AU - Fisher, L. Mark

AU - Fuller, John

AU - Fulsunder, Mangesh

AU - Holder, Lauren M.

AU - Hu, Cheng

AU - Kantariya, Bhavin

AU - Lapointe, Guillaume

AU - Leeds, Jennifer A.

AU - Li, Xiaolin

AU - Lu, Peichao

AU - Lvov, Anatoli

AU - Ma, Sylvia

AU - Madhavan, Shravanthi

AU - Malekar, Swapnil

AU - Mckenney, David

AU - Mergo, Wosenu

AU - Metzger, Louis

AU - Moser, Heinz E.

AU - Mutnick, Daniel

AU - Noeske, Jonas

AU - Osborne, Colin

AU - Patel, Ashish

AU - Patel, Darshit

AU - Patel, Tushar

AU - Prajapati, Krunal

AU - Prosen, Katherine R.

AU - Reck, Folkert

AU - Richie, Daryl L.

AU - Rico, Alice

AU - Sanderson, Mark R.

AU - Satasia, Shailesh

AU - Sawyer, William S.

AU - Selvarajah, Jogitha

AU - Shah, Nirav

AU - Shanghavi, Kartik

AU - Shu, Wei

AU - Thompson, Katherine V.

AU - Veselkov, Dennis A.

AU - Williams, Sarah L.

AU - Xu, Yongjin

AU - Yue, Qin

AU - Zang, Richard

AU - Zho, Bo

AU - Rivkin, Alexey

PY - 2020/7/23

Y1 - 2020/7/23

N2 - Since their discovery over 5 decades ago, quinolone antibiotics have found enormous success as broad spectrum agents that exert their activity through dual inhibition of bacterial DNA gyrase and topoisomerase IV. Increasing rates of resistance, driven largely by target-based mutations in the GyrA/ParC quinolone resistance determining region, have eroded the utility and threaten the future use of this vital class of antibiotics. Herein we describe the discovery and optimization of a series of 4-(aminomethyl)quinolin-2(1H)-ones, exemplified by 34, that inhibit bacterial DNA gyrase and topoisomerase IV and display potent activity against ciprofloxacin-resistant Gram-negative pathogens. X-ray crystallography reveals that 34 occupies the classical quinolone binding site in the topoisomerase IV-DNA cleavage complex but does not form significant contacts with residues in the quinolone resistance determining region.

AB - Since their discovery over 5 decades ago, quinolone antibiotics have found enormous success as broad spectrum agents that exert their activity through dual inhibition of bacterial DNA gyrase and topoisomerase IV. Increasing rates of resistance, driven largely by target-based mutations in the GyrA/ParC quinolone resistance determining region, have eroded the utility and threaten the future use of this vital class of antibiotics. Herein we describe the discovery and optimization of a series of 4-(aminomethyl)quinolin-2(1H)-ones, exemplified by 34, that inhibit bacterial DNA gyrase and topoisomerase IV and display potent activity against ciprofloxacin-resistant Gram-negative pathogens. X-ray crystallography reveals that 34 occupies the classical quinolone binding site in the topoisomerase IV-DNA cleavage complex but does not form significant contacts with residues in the quinolone resistance determining region.

UR - http://www.scopus.com/inward/record.url?scp=85088009200&partnerID=8YFLogxK

U2 - 10.1021/acs.jmedchem.0c00347

DO - 10.1021/acs.jmedchem.0c00347

M3 - Article

SN - 0022-2623

VL - 63

SP - 7773

EP - 7816

JO - Journal of Medicinal Chemistry

JF - Journal of Medicinal Chemistry

IS - 14

ER -

Topoisomerase Inhibitors Addressing Fluoroquinolone Resistance in Gram-Negative Bacteria

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