Structural basis of topoisomerase targeting by delafloxacin

Introduction

Fluoroquinolones are an important class of antimicrobial drugs that target topoisomerase (topo) IV and DNA gyrase, the type IIA topoisomerases (Top2As) essential for bacterial growth (Fig. 1 and Supplementary Fig. 1)^1,2. The attractive properties of fluoroquinolones are their oral availability, clinical potency, and activity against a wide range of bacterial pathogens¹. Given these features, the World Health Organisation has designated fluoroquinolones as one of five antimicrobial drug classes critical to the management of human disease³. Currently, ciprofloxacin, levofloxacin and moxifloxacin are the fluoroquinolones in widest clinical use and have recently been joined by delafloxacin, a novel drug with a chemically distinct structure (Fig. 1)¹.

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Fig. 1

Chemical structures of fluoroquinolones.

Structures of the clinically important fluoroquinolones delafloxacin, levofloxacin, moxifloxacin and ciprofloxacin are shown alongside clinafloxacin and trovafloxacin, two potent investigational agents.

Delafloxacin (ABT-492, Baxdela^R, Quofenix^R) is a unique anionic fluoroquinolone with impressive activity against Gram-positive and Gram-negative pathogens as well as anaerobes⁴. The drug was approved in 2017 for the treatment of bacterial skin/skin structure infections later extended to community acquired pneumonia⁴. S. pneumoniae, also known as the pneumococcus, is the main cause of community acquired pneumonia and is also an important pathogen in meningitis and sepsis⁴. Pneumococcal pneumonia affects the very young and old with an estimated one million deaths worldwide in children under five and the problem of drug-resistant disease^5,6.

Delafloxacin is a potent antibacterial agent that shares the 4-quinolone/naphthyridone core common to all fluoroquinolones but differs in three unusual structural features. First, it has a large heteroaromatic group at N-1 and a neighbouring C-8 chlorine that increase its activity in vitro (Fig. 1) and that re-establish efficacy against bacteria resistant to other therapeutic fluoroquinolones^4,7,8. Second, the absence of a protonable substituent at C-7 means that the anionic drug molecule has a single charge at physiological pH, but is charge neutral at mildly acidic pH, promoting greater bacterial uptake/accumulation and enhanced bacteriological activity^4,9. By contrast, the zwitterionic fluoroquinolones such as levofloxacin and moxifloxacin are positively charged at acidic pH, are taken up less readily and exhibit decreased activity under acidic conditions⁹....