title: In vitro activities of novel nonfluorinated quinolones PGE 9262932 and PGE 9509924 against clinical isolates of Staphylococcus aureus and Streptococcus pneumoniae with defined mutations in DNA gyrase and topoisomerase IV.
abstract: Two 8-methoxy nonfluorinated quinolones (NFQs), PGE 9262932 and PGE 9509924, were tested against contemporary clinical isolates of Staphylococcus aureus (n = 122) and Streptococcus pneumoniae (n = 69) with genetically defined quinolone resistance-determining regions (QRDRs). For S. aureus isolates with wild-type (WT) sequences at the QRDRs, the NFQs demonstrated activities 4- to 32-fold more potent (MICs at which 90% of isolates are inhibited [MIC(90)s], 0.03 microg/ml) than those of moxifloxacin (MIC(90), 0.12 microg/ml), gatifloxacin (MIC(90), 0.25 microg/ml), levofloxacin (MIC(90), 0.25 microg/ml), and ciprofloxacin (MIC(90), 1 microg/ml). Against S. pneumoniae isolates with WT sequences at gyrA and parC, the NFQs PGE 9262932 (MIC(90), 0.03 microg/ml) and PGE 9509924 (MIC(90), 0.12 microg/ml) were 8- to 64-fold and 2- to 16-fold more potent, respectively, than moxifloxacin (MIC(90), 0.25 microg/ml), gatifloxacin (MIC(90), 0.5 microg/ml), levofloxacin (MIC(90), 2 microg/ml), and ciprofloxacin (MIC(90), 2 microg/ml). The MICs of all agents were elevated for S. aureus isolates with alterations in GyrA (Glu88Lys or Ser84Leu) and GrlA (Ser80Phe) and S. pneumoniae isolates with alterations in GyrA (Ser81Phe or Ser81Tyr) and ParC (Ser79Phe or Lys137Asn). Fluoroquinolone MICs for S. aureus strains with double alterations in GyrA combined with double alterations in GrlA were > or =32 microg/ml, whereas the MICs of the NFQs for strains with these double alterations were 4 to 8 microg/ml. The PGE 9262932 and PGE 9509924 MICs for the S. pneumoniae isolates did not exceed 0.5 and 1 microg/ml, respectively, even for isolates with GyrA (Ser81Phe) and ParC (Ser79Phe) alterations, for which levofloxacin MICs were > 16 microg/ml. No difference in the frequency of selection of mutations (< 10(-8) at four times the MIC) in wild-type or first-step mutant isolates of S. aureus or S. pneumoniae was detected for the two NFQs. On the basis of their in vitro activities, these NFQ agents show potential for the treatment of infections caused by isolates resistant to currently available fluoroquinolones.
authors.affiliation: Focus Technologies, Hilversum, The Netherlands. Focus Technologies, Herndon, Virginia, USA. mjones@focusanswers.com
authors.forename: Mark E
authors.initials: ME
authors.lastname: Jones
authors.forename: Ian A
authors.initials: IA
authors.lastname: Critchley
authors.forename: James A
authors.initials: JA
authors.lastname: Karlowsky
authors.forename: Renée S
authors.initials: RS
authors.lastname: Blosser-Middleton
authors.forename: Franz-Josef
authors.initials: FJ
authors.lastname: Schmitz
authors.forename: Clyde
authors.initials: C
authors.lastname: Thornsberry
authors.forename: Daniel F
authors.initials: DF
authors.lastname: Sahm
mesh_terms: D000890:Anti-Infective Agents / Q000494:pharmacology*; D027081:DNA Gyrase / Q000235:genetics / Q000378:metabolism*; D027101:DNA Topoisomerase IV / Q000235:genetics / Q000378:metabolism*; D004269:DNA, Bacterial / Q000235:genetics; D006801:Humans; D008826:Microbial Sensitivity Tests; D009154:Mutation / Q000235:genetics; D015363:Quinolones / Q000494:pharmacology*; D013203:Staphylococcal Infections / Q000382:microbiology; D013211:Staphylococcus aureus / Q000187:drug effects* / Q000201:enzymology / Q000235:genetics; D013290:Streptococcal Infections / Q000382:microbiology; D013296:Streptococcus pneumoniae / Q000187:drug effects* / Q000201:enzymology / Q000235:genetics
chemical_list: D000890:Anti-Infective Agents; D004269:DNA, Bacterial; C466660:PGE 9262932; C466659:PGE 9509924; D015363:Quinolones; D027101:DNA Topoisomerase IV; D027081:DNA Gyrase