TABLE 3

Summary of gyrase inhibitors tested for Qnr protection

Compound(s)TargetStabilization of covalent complexATPase inhibitionInhibition of topoisomerase IVResistance mutations (in E. coli unless otherwise specified)Qnr ProtectionReference(s)
CcdBBinds as a dimer to the dimerization domain of GyrA while strand passage takes placeYesNoGyrA mutation at amino acid 462 with no cross-resistance with quinoloneNo3739, 50
Coumermycin A1Competitve inhibitor of GyrB and ParE ATPase activityNoYesYesGyrB mutations at sites other than those associated with quinolone resistance: amino acids 73, 77, 136, 164, and 165No34, 35, 51, 52
Gyramide ACompetitive inhibitor of GyrB ATPase activityNoYesNoAt sites in GyrA (amino acids 34, 35, 45, 96, 97, 98, 169, 170, 172, 173, 267, and 335) and GyrB (amino acid 508) without effect on quinolone or novobiocin susceptibilityNo11, 53
Microcin B17Binds to C-terminal domain of GyrB, slowing DNA strand passageYesNoGyrB mutation at amino acid 751 confers resistance, but some quinolone resistance mutations at amino acid 83 in GyrA or amino acid 447 in GyrB provide partial resistanceNo12, 54, 55
NovobiocinCompetitve inhibitor of GyrB and ParE ATPase activityNoYesYesGyrB mutations at sites other than those associated with quinolone resistance: amino acids 73, 77, 136, 164, and 165No16, 34, 35, 51, 52
ParE toxinDNA gyraseYesNo37, 56
Simocyclinone D8N-terminal domain of GyrA, preventing DNA binding. Second weak binding site on C terminus of GyrB.NoNoNoGyrA mutations (amino acids 42, 44, 45, 80, 81, 83, 84, 87, 91, and 120), some of which confer quinolone resistanceNo13, 14, 26, 5759
ABT-719DNA gyraseYesYes19
PD 0305970DNA gyraseYesYesIn S. pneumoniae mutations in toprim domain of GyrB at amino acids 456 and 474 or in ParE at 435 and 475. No cross-resistance with several quinolone resistance mutations.Yes21, 22, 30
PATDNA gyraseYesNo cross-resistance with quinolones in S. aureus or S. pneumoniaeYes23, 60, 61
PyrazolopyridonesGyrBNo25
QuinolonesGyrA, ParC, GyrB, ParE with gyrase more susceptible than topoisomerase IV for E. coliYesNoYesQRDR GyrA: amino acids 51, 67, 81, 82, 83, 84, 87, and 106. QRDR GyrB: amino acids 426 and 447. QRDR ParC: amino acids 78, 80, and 84. QRDR ParE: amino acid 445.Yes35, 32
Tricyclic pyrimidoindolesGyrB and ParE at the ATP binding siteYesYesNo24