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Antimicrobial Agents and Chemotherapy, August 2003, p. 2584-2589, Vol. 47, No. 8
0066-4804/03/$08.00+0     DOI: 10.1128/AAC.47.8.2584-2589.2003
Copyright © 2003, American Society for Microbiology. All Rights Reserved.

Heme Binding Contributes to Antimalarial Activity of Bis-Quaternary Ammoniums

Giancarlo A. Biagini,1 Eric Richier,2 Patrick G. Bray,1 Michèle Calas,3 Henri Vial,2 and Stephen A. Ward1*

Liverpool School of Tropical Medicine, Liverpool, L35 QA, United Kingdom,1 CNRS UMR 5539, CP 107,2 CNRS UMR 5810, CP 22, Université Montpellier II, 34095 Montpellier Cedex 05, France3

Received 28 March 2003/ Returned for modification 4 May 2003/ Accepted 19 May 2003

Quaternary ammonium compounds have received recent attention due to their potent in vivo antimalarial activity based on their ability to inhibit de novo phosphatidylcholine synthesis. Here we show that in addition to this, heme binding significantly contributes to the antimalarial activity of these compounds. For the study, we used a recently synthesized bis-quaternary ammonium compound, T16 (1,12-dodecanemethylene bis[4-methyl-5-ethylthiazolium] diodide), which exhibits potent antimalarial activity (50% inhibitory concentration, ~25 nM). Accumulation assays reveal that this compound is readily concentrated several hundredfold (cellular accumulation ratio, ~500) into parasitized erythrocytes. Approximately 80% of the drug was shown to be distributed within the parasite, ~50% of which was located in the parasite food vacuoles. T16 uptake was affected by anion substitution (permeation increasing in the order Cl- < Br- = NO3- < I- < SCN-) and was sensitive to furosemide—properties similar to substrates of the induced new permeability pathway in infected erythrocytes. Scatchard plot analysis of in situ T16 binding revealed high-affinity and low-affinity binding sites. The high-affinity binding site Kd was similar to that measured in vitro for T16 and ferriprotoporphyrin IX (FPIX) binding. Significantly, the capacity but not the Kd of the high-affinity binding site was decreased by reducing the concentration of parasite FPIX. Decreasing the parasite FPIX pool also caused a marked antagonism of T16 antimalarial activity. In addition, T16 was also observed to associate with parasite hemozoin. Binding of T16 to FPIX in the digestive food vacuole is shown to be critical for drug accumulation and antimalarial activity. These data provide additional new mechanisms of antimalarial activity for this promising new class of antimalarial compounds.

* Corresponding author. Mailing address: Liverpool School of Tropical Medicine, Pembroke Place, Liverpool, L35 QA, United Kingdom. Phone: 44 (0) 151 705 3286. Fax: 44 (0) 151 705 3371. E-mail: saward{at}liv.ac.uk.

Antimicrobial Agents and Chemotherapy, August 2003, p. 2584-2589, Vol. 47, No. 8
0066-4804/03/$08.00+0     DOI: 10.1128/AAC.47.8.2584-2589.2003
Copyright © 2003, American Society for Microbiology. All Rights Reserved.



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