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Antimicrobial Agents and Chemotherapy, April 2009, p. 1353-1361, Vol. 53, No. 4
0066-4804/09/$08.00+0     doi:10.1128/AAC.01619-08
Copyright © 2009, American Society for Microbiology. All Rights Reserved.

Antistaphylococcal Activity of Dihydrophthalazine Antifolates, a Family of Novel Antibacterial Drugs {triangledown}

Catherine Clark,1 Lois M. Ednie,1 Gengrong Lin,1 Kathy Smith,1 Klaudia Kosowska-Shick,1 Pamela McGhee,1 Bonifacio Dewasse,1 Linda Beachel,1 Patrick Caspers,2 Bérangère Gaucher,2 Gürkan Mert,1 Stuart Shapiro,2 and Peter C. Appelbaum1*

Department of Pathology, Hershey Medical Center, Hershey, Pennsylvania 17033,1 Basilea Pharmaceutica International AG, Basel, Switzerland2

Received 8 December 2008/ Returned for modification 19 January 2009/ Accepted 22 January 2009

For a panel of 153 Staphylococcus aureus clinical isolates (including 13 vancomycin-intermediate or heterogeneous vancomycin-intermediate and 4 vancomycin-resistant strains), MIC50s and MIC90s of three novel dihydrophthalazine antifolates, BAL0030543, BAL0030544, and BAL0030545, were 0.03 and 0.25 µg/ml, respectively, for methicillin-susceptible strains and 0.03 and ≤0.25 µg/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), MIC50s and MIC90s were ≤0.03 and ≤0.06 µg/ml, respectively, for methicillin-susceptible strains and 0.06 and 0.5 µg/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 µg/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.

* Corresponding author. Mailing address: Department of Pathology, Hershey Medical Center, P.O. Box 850, Hershey, PA 17033. Phone: (717) 531-5113. Fax: (717) 531-7953. E-mail: pappelbaum{at}psu.edu

{triangledown} Published ahead of print on 2 February 2009.

Antimicrobial Agents and Chemotherapy, April 2009, p. 1353-1361, Vol. 53, No. 4
0066-4804/09/$08.00+0     doi:10.1128/AAC.01619-08
Copyright © 2009, American Society for Microbiology. All Rights Reserved.



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  • Caspers, P., Bury, L., Gaucher, B., Heim, J., Shapiro, S., Siegrist, S., Schmitt-Hoffmann, A., Thenoz, L., Urwyler, H. (2009). In Vitro and In Vivo Properties of Dihydrophthalazine Antifolates, a Novel Family of Antibacterial Drugs. Antimicrob. Agents Chemother. 53: 3620-3627 [Abstract] [Full Text]  


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