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Antimicrobial Agents and Chemotherapy, November 2001, p. 3175-3181, Vol. 45, No. 11
0066-4804/01/$04.00+0   DOI: 10.1128/AAC.45.11.3175-3181.2001
Copyright © 2001, American Society for Microbiology. All rights reserved.

Analysis of Antimalarial Synergy between Bestatin and Endoprotease Inhibitors Using Statistical Response-Surface Modelling

Clare S. Gavigan,¹ Stella G. Machado,² John P. Dalton,³ and Angus Bell^1,*

Department of Microbiology, Trinity College,¹ and School of Biotechnology, Dublin City University,³ Dublin, Ireland, and Center for Drug Evaluation and Research, Food and Drug Administration, Rockville, Maryland²

Received 17 November 2000/Returned for modification 19 May 2001/Accepted 24 July 2001

The pathway of hemoglobin degradation by erythrocytic stages of the human malarial parasite Plasmodium falciparum involves initial cleavages of globin chains, catalyzed by several endoproteases, followed by liberation of amino acids from the resulting peptides, probably by aminopeptidases. This pathway is considered a promising chemotherapeutic target, especially in view of the antimalarial synergy observed between inhibitors of aspartyl and cysteine endoproteases. We have applied response-surface modelling to assess antimalarial interactions between endoprotease and aminopeptidase inhibitors using cultured P. falciparum parasites. The synergies observed were consistent with a combined role of endoproteases and aminopeptidases in hemoglobin catabolism in this organism. As synergies between antimicrobial agents are often inferred without proper statistical analysis, the model used may be widely applied in studies of antimicrobial drug interactions.

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^* Corresponding author. Mailing address: Department of Microbiology, Moyne Institute, Trinity College, Dublin 2, Ireland. Phone: (353 1) 608 1414. Fax: (353 1) 679 9294. E-mail: abell{at}tcd.ie.

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Antimicrobial Agents and Chemotherapy, November 2001, p. 3175-3181, Vol. 45, No. 11
0066-4804/01/$04.00+0   DOI: 10.1128/AAC.45.11.3175-3181.2001
Copyright © 2001, American Society for Microbiology. All rights reserved.

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