Structural basis of quinolone inhibition of type IIA topoisomerases and target-mediated resistance

  title={Structural basis of quinolone inhibition of type IIA topoisomerases and target-mediated resistance},
  author={Alexandre Wohlkonig and Pan F. Chan and Andrew P. Fosberry and Paul Homes and Jianzhong Huang and Michael Kranz and Vaughan R. Leydon and Timothy J Miles and Neil David GlaxoSmithKline Pearson and Rajika L Perera and Anthony Shillings and Michael N. Gwynn and Benjamin D. Bax},
  journal={Nature Structural \&Molecular Biology},
  • A. Wohlkonig, P. Chan, +10 authors B. Bax
  • Published 1 September 2010
  • Biology, Chemistry, Medicine
  • Nature Structural &Molecular Biology
Quinolone antibacterials have been used to treat bacterial infections for over 40 years. A crystal structure of moxifloxacin in complex with Acinetobacter baumannii topoisomerase IV now shows the wedge-shaped quinolone stacking between base pairs at the DNA cleavage site and binding conserved residues in the DNA cleavage domain through chelation of a noncatalytic magnesium ion. This provides a molecular basis for the quinolone inhibition mechanism, resistance mutations and invariant quinolone… Expand
Topoisomerase Inhibitors Addressing Fluoroquinolone Resistance in Gram-Negative Bacteria.
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 are described. Expand
New developments in non-quinolone-based antibiotics for the inhibiton of bacterial gyrase and topoisomerase IV.
The last five years progress of various classes of non-quinolone-based chemical compounds that are tested for their antibacterial activities are reviewed. Expand
Novel quinoline derivatives as inhibitors of bacterial DNA gyrase and topoisomerase IV.
A structurally novel set of inhibitors of bacterial type II topoisomerases with potent in vitro and in vivo antibacterial activity was developed. Dual-targeting ability, hERG inhibition, andExpand
Selenophene-containing inhibitors of type IIA bacterial topoisomerases.
Two compounds related to the previously reported antistaphyloccocal agent AVE6971 displayed improved activity against the primary target enzyme DNA gyrase, similar activities against a panel of MRSA clinical isolates, and reduced hERG channel inhibition. Expand
Molecular Simulations Highlight the Role of Metals in Catalysis and Inhibition of Type II Topoisomerase.
This model describes a canonical two-metal-ion mechanism and suggests how the metals could rearrange at the catalytic pocket during enzymatic turnover, explaining also experimental evidence for topoII inhibition. Expand
Rational design, synthesis and testing of novel tricyclic topoisomerase inhibitors for the treatment of bacterial infections part 1.
A series of DNA gyrase and topoisomerase IV inhibitors that demonstrate potent activity against a range of Gram-positive and selected Gram-negative organisms, including clinically-relevant and drug-resistant strains are reported. Expand
Topoisomerase Inhibitors: Fluoroquinolone Mechanisms of Action and Resistance.
Mechanisms of resistance include mutational alterations in drug target affinity and efflux pump expression and acquisition of resistance-conferring genes and resistance genes acquired on plasmids confer low-level resistance that promotes the selection of mutational high- level resistance. Expand
Antibacterial action of quinolones: from target to network.
Molecular basis for the antibacterial action of quinolones, from target to network, is fully discussed and updated and will provide new targets for drug design and approaches to prevent bacterial resistance. Expand
Recent Developments in Inhibitors of Bacterial Type IIA Topoisomerases
Type II topoisomerases are a family of molecular machines, present in all cells, which choreograph a complex multistep catalytic cycle to transform DNA topology. Double‐stranded DNA cleavage, strandExpand
DNA Topoisomerases as Targets for Antibacterial Agents.
  • H. Hiasa
  • Chemistry, Medicine
  • Methods in molecular biology
  • 2018
DNA topoisomerases are proven therapeutic targets of antibacterial agents and may lead to the development of novel antibacterial drugs that are effective against fluoroquinolone-resistant pathogens. Expand


Type IIA topoisomerase inhibition by a new class of antibacterial agents
This work provides new insights into the mechanism of topoisomerase action and a platform for structure-based drug design of a new class of antibacterial agents against a clinically proven, but conformationally flexible, enzyme class. Expand
Structural insight into the quinolone–DNA cleavage complex of type IIA topoisomerases
The structures of cleavage complexes formed by the Streptococcus pneumoniae ParC breakage-reunion and ParE TOPRIM domains of topoisomerase IV stabilized by moxifloxacin and clinafloxacIn help explain antibacterial quinolone action and resistance. Expand
Hot-spot consensus of fluoroquinolone-mediated DNA cleavage by Gram-negative and Gram-positive type II DNA topoisomerases
Analysis on the wild-type and mutated consensus sequences showed that Gn/Cn-rich sequences at and around the cleavage site are hot spots for quinolone-mediated strand breaks, especially for E. coli topoisomerases. Expand
Structural basis for gate-DNA recognition and bending by type IIA topoisomerases
The structure of a complex between the DNA-binding and cleavage core of Saccharomyces cerevisiae Topo II and a gate-DNA segment is presented, revealing that the enzyme enforces a 150° DNA bend through a mechanism similar to that of remodelling proteins such as integration host factor. Expand
Structural Basis of Gate-DNA Breakage and Resealing by Type II Topoisomerases
X-ray crystallography is used to study sequential states in the formation and reversal of a DNA cleavage complex by topoisomerase IV from Streptococcus pneumoniae, the bacterial type II enzyme involved in chromosome segregation to suggest how a type II enzymes reseals DNA during its normal reaction cycle and illuminate aspects of drug arrest important for the development of new topoisomersase-targeting therapeutics. Expand
Drugs for bad bugs: confronting the challenges of antibacterial discovery
The experience of evaluating more than 300 genes and 70 high-throughput screening campaigns over a period of 7 years is shared, and what is learned is looked at and how that has influenced GlaxoSmithKline's antibacterials strategy going forward. Expand
Ciprofloxacin affects conformational equilibria of DNA gyrase A in the presence of magnesium ions.
The data suggest that ciprofloxacin binds to the wild-type subunit in an interaction that involves Ser83 of GyrA and that both C and N-terminal domains may be required for effective drug-protein interactions, and that the Mg(2+)-mediated quinolone binding to the enzyme might be involved in the mechanism of action of this family of drugs. Expand
Quinolone antimicrobial agents
The role of quinolones in treatment of chronic bacterial prostatitis and septic arthritis and their effects on the central nervous system and immune system are studied. Expand
Bacterial topoisomerase inhibitors: quinolone and pyridone antibacterial agents.
3.1. Chelation 564 3.2. Acid−Base Character 564 3.3. Photochemistry 565 4. In Vitro Antimicrobial Spectra 566 5. Structure−Activity Relationships 568 5.1. N-1 Ethyl Family 568 5.2. N-1 CyclopropylExpand
X-Ray crystallographic, NMR and antimicrobial activity studies of magnesium complexes of fluoroquinolones - racemic ofloxacin and its S-form, levofloxacin.
The antimicrobial activity of the magnesium complexes against various microorganisms was tested and it was established that their activity is similar to that of free quinolone drugs. Expand