Antistaphylococcal activity of dihydrophthalazine antifolates, a family of novel antibacterial drugs.
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.
Clark
Catherine
C
Department of Pathology, Hershey Medical Center, Hershey, Pennsylvania 17033, USA.
Ednie
Lois M
LM
Lin
Gengrong
G
Smith
Kathy
K
Kosowska-Shick
Klaudia
K
McGhee
Pamela
P
Dewasse
Bonifacio
B
Beachel
Linda
L
Caspers
Patrick
P
Gaucher
Bérangère
B
Mert
Gürkan
G
Shapiro
Stuart
S
Appelbaum
Peter C
PC
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
D000900:Anti-Bacterial Agents; D005493:Folic Acid Antagonists; D010793:Phthalazines; D013762:Tetrahydrofolate Dehydrogenase