Skip to Content
Merck
  • Topoisomerase IV-quinolone interactions are mediated through a water-metal ion bridge: mechanistic basis of quinolone resistance.

Topoisomerase IV-quinolone interactions are mediated through a water-metal ion bridge: mechanistic basis of quinolone resistance.

Nucleic acids research (2013-03-06)
Katie J Aldred, Sylvia A McPherson, Charles L Turnbough, Robert J Kerns, Neil Osheroff
ABSTRACT

Although quinolones are the most commonly prescribed antibacterials, their use is threatened by an increasing prevalence of resistance. The most common causes of quinolone resistance are mutations of a specific serine or acidic residue in the A subunit of gyrase or topoisomerase IV. These amino acids are proposed to serve as a critical enzyme-quinolone interaction site by anchoring a water-metal ion bridge that coordinates drug binding. To probe the role of the proposed water-metal ion bridge, we characterized wild-type, GrlA(E85K), GrlA(S81F/E85K), GrlA(E85A), GrlA(S81F/E85A) and GrlA(S81F) Bacillus anthracis topoisomerase IV, their sensitivity to quinolones and related drugs and their use of metal ions. Mutations increased the Mg(2+) concentration required to produce maximal quinolone-induced DNA cleavage and restricted the divalent metal ions that could support quinolone activity. Individual mutation of Ser81 or Glu85 partially disrupted bridge function, whereas simultaneous mutation of both residues abrogated protein-quinolone interactions. Results provide functional evidence for the existence of the water-metal ion bridge, confirm that the serine and glutamic acid residues anchor the bridge, demonstrate that the bridge is the primary conduit for interactions between clinically relevant quinolones and topoisomerase IV and provide a likely mechanism for the most common causes of quinolone resistance.

MATERIALS
Product Number
Brand
Product Description

Supelco
Ciprofloxacin HCl, Pharmaceutical Secondary Standard; Certified Reference Material
Pricing and availability is not currently available.
Supelco
Ciprofloxacin, VETRANAL®, analytical standard
Pricing and availability is not currently available.
Supelco
Ciprofloxacin, Pharmaceutical Secondary Standard; Certified Reference Material
Pricing and availability is not currently available.
Sigma-Aldrich
Ciprofloxacin, ≥98% (HPLC)
Pricing and availability is not currently available.
Ciprofloxacin, European Pharmacopoeia (EP) Reference Standard
Pricing and availability is not currently available.
Ciprofloxacin hydrochloride for peak identification, European Pharmacopoeia (EP) Reference Standard
Pricing and availability is not currently available.
Ciprofloxacin hydrochloride, European Pharmacopoeia (EP) Reference Standard
Pricing and availability is not currently available.