title: Antistaphylococcal activity of dihydrophthalazine antifolates, a family of novel antibacterial drugs.
abstract: For a panel of 153 Staphylococcus aureus clinical isolates (including 13 vancomycin-intermediate or heterogeneous vancomycin-intermediate and 4 vancomycin-resistant strains), MIC(50)s and MIC(90)s of three novel dihydrophthalazine antifolates, BAL0030543, BAL0030544, and BAL0030545, were 0.03 and 0.25 microg/ml, respectively, for methicillin-susceptible strains and 0.03 and <or=0.25 microg/ml, respectively, for methicillin-resistant strains. For a panel of 160 coagulase-negative staphylococci (including 5 vancomycin-intermediate and heterogeneous vancomycin-intermediate strains and 7 linezolid-nonsusceptible strains), MIC(50)s and MIC(90)s were <or=0.03 and <or=0.06 microg/ml, respectively, for methicillin-susceptible strains and 0.06 and 0.5 microg/ml, respectively, for methicillin-resistant strains. Vancomycin was active against 93.0% of 313 staphylococci examined; linezolid was active against all S. aureus strains and 95.6% of coagulase-negative staphylococcus strains, whereas elevated MICs of clindamycin, minocycline, trimethoprim, and rifampin for some strains were observed. At 4x MIC, the dihydrophthalazines were bactericidal against 11 of 12 staphylococcal strains surveyed. The prolonged serial passage of some staphylococcal strains in the presence of subinhibitory concentrations of BAL0030543, BAL0030544, and BAL0030545 produced clones for which dihydrophthalazines showed high MICs (>128 microg/ml), although rates of endogenous resistance development were much lower for the dihydrophthalazines than for trimethoprim. Single-step platings of naïve staphylococci onto media containing dihydrophthalazine antifolates indicated considerable variability among strains with respect to preexistent subpopulations nonsusceptible to dihydrophthalazine antifolates.
authors.affiliation: Department of Pathology, Hershey Medical Center, Hershey, Pennsylvania 17033, USA.
authors.forename: Catherine
authors.initials: C
authors.lastname: Clark
authors.forename: Lois M
authors.initials: LM
authors.lastname: Ednie
authors.forename: Gengrong
authors.initials: G
authors.lastname: Lin
authors.forename: Kathy
authors.initials: K
authors.lastname: Smith
authors.forename: Klaudia
authors.initials: K
authors.lastname: Kosowska-Shick
authors.forename: Pamela
authors.initials: P
authors.lastname: McGhee
authors.forename: Bonifacio
authors.initials: B
authors.lastname: Dewasse
authors.forename: Linda
authors.initials: L
authors.lastname: Beachel
authors.forename: Patrick
authors.initials: P
authors.lastname: Caspers
authors.forename: Bérangère
authors.initials: B
authors.lastname: Gaucher
authors.forename: Gürkan
authors.initials: G
authors.lastname: Mert
authors.forename: Stuart
authors.initials: S
authors.lastname: Shapiro
authors.forename: Peter C
authors.initials: PC
authors.lastname: Appelbaum
mesh_terms: D000900:Anti-Bacterial Agents / Q000494:pharmacology*; D024881:Drug Resistance, Bacterial; D005493:Folic Acid Antagonists / Q000494:pharmacology*; D008826:Microbial Sensitivity Tests; D010793:Phthalazines / Q000494:pharmacology*; D013211:Staphylococcus aureus / Q000187:drug effects*; D013212:Staphylococcus epidermidis / Q000187:drug effects*; D013762:Tetrahydrofolate Dehydrogenase / Q000235:genetics
chemical_list: D000900:Anti-Bacterial Agents; D005493:Folic Acid Antagonists; D010793:Phthalazines; D013762:Tetrahydrofolate Dehydrogenase