Discovery and Optimization of DNA Gyrase and Topoisomerase IV Inhibitors with Potent Activity against Fluoroquinolone-Resistant Gram-Positive Bacteria.
Lapointe G, Skepper CK, Holder LM, Armstrong D, Bellamacina C, Blais J, Bussiere D, Bian J, Cepura C, Chan H, Dean CR, De Pascale G, Dhumale B, Fisher LM, Fulsunder M, Kantariya B, Kim J, King S, Kossy L, Kulkarni U, Lakshman J, Leeds JA, Ling X, Lvov A, Ma S, Malekar S, McKenney D, Mergo W, Metzger L, Mhaske K, Moser HE, Mostafavi M, Namballa S, Noeske J, Osborne C, Patel A, Patel D, Patel T, Piechon P, Polyakov V, Prajapati K, Prosen KR, Reck F, Richie DL, Sanderson MR, Satasia S, Savani B, Selvarajah J, Sethuraman V, Shu W, Tashiro K, Thompson KV, Vaarla K, Vala L, Veselkov DA, Vo J, Vora B, Wagner T, Wedel L, Williams SL, Yendluri S, Yue Q, Yifru A, Zhang Y, Rivkin A.
Herein, we describe the discovery and optimization of a novel series that inhibits bacterial DNA gyrase and topoisomerase IV <i>via</i> binding to, and stabilization of, DNA cleavage complexes. Optimization of this series led to the identification of compound <b>25</b>, which has potent activity against Gram-positive bacteria, a favorable <i>in vitro</i> safety profile, and excellent <i>in vivo</i> pharmacokinetic properties. Compound <b>25</b> was found to be efficacious against fluoroquinolone-sensitive <i>Staphylococcus aureus</i> 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 <i>Klebsiella pneumoniae</i>, compound <b>25</b>, 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 <b>25</b> compared to fluoroquinolones.