Discovery and Optimization of DNA Gyrase and Topoisomerase IV Inhibitors with Potent Activity against Fluoroquinolone-Resistant Gram-Positive Bacteria

J Med Chem. 2021 May 13;64(9):6329-6357. doi: 10.1021/acs.jmedchem.1c00375.

Guillaume Lapointe ¹, Colin K Skepper ¹, Lauren M Holder ¹, Duncan Armstrong ², Cornelia Bellamacina ¹, Johanne Blais ¹, Dirksen Bussiere ¹, Jianwei Bian ³, Cody Cepura ¹, Helen Chan ¹, Charles R Dean ¹, Gianfranco De Pascale ¹, Bhavesh Dhumale ⁴, L Mark Fisher ⁵, Mangesh Fulsunder ⁴, Bhavin Kantariya ⁴, Julie Kim ¹, Sean King ¹, Lauren Kossy ¹, Upendra Kulkarni ¹, Jay Lakshman ⁶, Jennifer A Leeds ¹, Xiaolan Ling ³, Anatoli Lvov ², Sylvia Ma ¹, Swapnil Malekar ¹, David McKenney ¹, Wosenu Mergo ¹, Louis Metzger ¹, Keshav Mhaske ⁴, Heinz E Moser ¹, Mina Mostafavi ¹, Sunil Namballa ⁴, Jonas Noeske ¹, Colin Osborne ¹, Ashish Patel ⁴, Darshit Patel ⁴, Tushar Patel ⁴, Philippe Piechon ⁷, Valery Polyakov ¹, Krunal Prajapati ⁴, Katherine R Prosen ¹, Folkert Reck ¹, Daryl L Richie ¹, Mark R Sanderson ⁸, Shailesh Satasia ⁴, Bhautik Savani ⁴, Jogitha Selvarajah ⁵, Vijay Sethuraman ¹, Wei Shu ¹, Kyuto Tashiro ¹, Katherine V Thompson ¹, Krishniah Vaarla ⁴, Lakhan Vala ⁴, Dennis A Veselkov ⁸, Jason Vo ¹, Bhavesh Vora ⁴, Trixie Wagner ⁷, Laura Wedel ¹, Sarah L Williams ¹, Satya Yendluri ¹, Qin Yue ¹, Aregahegn Yifru ¹, Yong Zhang ³, Alexey Rivkin ¹

Affiliations

1 Novartis Institutes for BioMedical Research, Emeryville, California 94608, United States.
2 Novartis Institutes for BioMedical Research, Cambridge, Massachusetts 02139, United States.
3 Novartis Global Drug Development, Pudong, Shanghai 201203, China.
4 Piramal Discovery Solutions, Pharmaceutical Special Economic Zone, Sarkhej Bavla Highway, Ahmedabad, Gujarat 382213, India.
5 Molecular and Clinical Sciences Research Institute, St George's, University of London, London SW17 0RE, U.K.
6 Novartis Global Drug Development, East Hanover, New Jersey 07936, United States.
7 Novartis Institutes for BioMedical Research, Basel 4002, Switzerland.
8 Randall Centre for Cell and Molecular Biophysics, King's College, Guy's Campus, London Bridge, London SE1 1UL, U.K.

PMID: 33929852 DOI: 10.1021/acs.jmedchem.1c00375

Abstract

Herein, we describe the discovery and optimization of a novel series that inhibits Bacterial DNA gyrase and Topoisomerase IV via binding to, and stabilization of, DNA cleavage complexes. Optimization of this series led to the identification of compound 25, which has potent activity against Gram-positive bacteria, a favorable in vitro safety profile, and excellent in vivo pharmacokinetic properties. Compound 25 was found to be efficacious against fluoroquinolone-sensitive Staphylococcus aureus Infection in a mouse thigh model at lower doses than moxifloxacin. An X-ray crystal structure of the ternary complex formed by Topoisomerase IV from Klebsiella pneumoniae, compound 25, and cleaved DNA indicates that this compound does not engage in a water-metal ion bridge interaction and forms no direct contacts with residues in the Quinolone resistance determining region (QRDR). This suggests a structural basis for the reduced impact of QRDR mutations on Antibacterial activity of 25 compared to fluoroquinolones.

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