In vitro and in vivo properties of dihydrophthalazine antifolates, a novel family of antibacterial drugs.
Racemic 2,4-diaminopyrimidine dihydrophthalazine derivatives BAL0030543, BAL0030544, and BAL0030545 exhibited low in vitro MICs toward small, selected panels of Enterococcus faecalis, Enterococcus faecium, Streptococcus pneumoniae, Moraxella catarrhalis, and Mycobacterium avium, though the compounds were less active against Haemophilus influenzae. The constellation of dihydrofolate reductases (DHFRs) present in 20 enterococci and 40 staphylococci was analyzed and correlated with the antibacterial activities of the dihydrophthalazines and trimethoprim. DHFRs encoded by dfrB, dfrA (S1 isozyme), dfrE, and folA were susceptible to the dihydrophthalazines, whereas DHFRs encoded by dfrG (S3 isozyme) and dfrF were not. Studies with the separated enantiomers of BAL0030543, BAL0030544, and BAL0030545 revealed preferential inhibition of susceptible DHFRs by the (R)-enantiomers. BAL0030543, BAL0030544, and BAL0030545 were well tolerated by mice during 5- and 10-day oral toxicity studies at doses of up to 400 mg/kg of body weight. Using a nonoptimized formulation, the dihydrophthalazines displayed acceptable oral bioavailabilities in mice, and efficacy studies with a septicemia model of mice infected with trimethoprim-resistant, methicillin-resistant Staphylococcus aureus gave 50% effective dose values in the range of 1.6 to 6.25 mg/kg.
Caspers
Patrick
P
Basilea Pharmaceutica International AG, Postfach, CH-4005 Basel, Switzerland. patrick.caspers@basilea.com
Bury
Luc
L
Gaucher
Bérangère
B
Heim
Jutta
J
Shapiro
Stuart
S
Siegrist
Sibylle
S
Schmitt-Hoffmann
Anne
A
Thenoz
Laure
L
Urwyler
Heinrich
H
D000818:Animals; D000900:Anti-Bacterial Agents / Q000737:chemistry / Q000493:pharmacokinetics* / Q000494:pharmacology*; D002470:Cell Survival / Q000187:drug effects; D016983:Enterococcus / Q000187:drug effects / Q000201:enzymology; D005493:Folic Acid Antagonists / Q000737:chemistry / Q000493:pharmacokinetics* / Q000494:pharmacology*; D006193:Haemophilus influenzae / Q000187:drug effects / Q000201:enzymology; D006367:HeLa Cells; D006801:Humans; D008297:Male; D051379:Mice; D008826:Microbial Sensitivity Tests; D015394:Molecular Structure; D001936:Moraxella catarrhalis / Q000187:drug effects / Q000201:enzymology; D009162:Mycobacterium avium / Q000187:drug effects / Q000201:enzymology; D010793:Phthalazines / Q000737:chemistry / Q000493:pharmacokinetics* / Q000494:pharmacology*; D016133:Polymerase Chain Reaction; D013296:Streptococcus pneumoniae / Q000187:drug effects / Q000201:enzymology; D013762:Tetrahydrofolate Dehydrogenase / Q000235:genetics; D014295:Trimethoprim / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology*
D000900:Anti-Bacterial Agents; D005493:Folic Acid Antagonists; D010793:Phthalazines; D014295:Trimethoprim; D013762:Tetrahydrofolate Dehydrogenase