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Antimicrobial Agents and Chemotherapy, April 2008, p. 1438-1445, Vol. 52, No. 4
0066-4804/08/$08.00+0     doi:10.1128/AAC.01392-07
Copyright © 2008, American Society for Microbiology. All Rights Reserved.

Drug-Regulated Expression of Plasmodium falciparum P-Glycoprotein Homologue 1: a Putative Role for Nuclear Receptors{triangledown}

David J. Johnson,1* Andrew Owen,2 Nick Plant,3 Patrick G. Bray,1 and Stephen A. Ward1

Molecular and Biochemical Parasitology, Liverpool School of Tropical Medicine, Pembroke Place, Liverpool, Merseyside L3 5QA, United Kingdom,1 Department of Pharmacology and Therapeutics, 70 Pembroke Place, University of Liverpool, Liverpool L69 3GF, United Kingdom,2 Molecular Toxicology Group, School of Biomedical and Molecular Sciences, University of Surrey, Guildford, Surrey GU2 7XH, United Kingdom3

Received 29 October 2007/ Returned for modification 6 December 2007/ Accepted 3 January 2008

Acquired resistance to therapeutic agents is a major clinical concern in the prevention/treatment of malaria. The parasite has developed resistance to specific drugs through two mechanisms: mutations in target proteins such as dihydrofolate reductase and the bc1 complex for antifolates and nathoquinones, respectively, and alterations in predicted parasite transporter molecules such as P-glycoprotein homologue 1 (Pgh1) and Plasmodium falciparum CRT (PfCRT). Alterations in the expression of Pgh1 have been associated with modified susceptibility to a range of unrelated drugs. The molecular mechanism(s) that is responsible for this phenotype is unknown. We have shown previously (A. M. Ndifor, R. E. Howells, P. G. Bray, J. L. Ngu, and S. A. Ward, Antimicrob. Agents Chemother. 37:1318-1323, 2003) that the anticonvulsant phenobarbitone (PB) can induce reduced susceptibility to chloroquine (CQ) in P. falciparum, and in the current study, we provide the first evidence for a molecular mechanism underlying this phenomenon. We demonstrate that pretreatment with PB can elicit decreased susceptibility to CQ in both CQ-resistant and CQ-sensitive parasite lines and that this is associated with the increased expression of the drug transporter Pgh1 but not PfCRT. Furthermore, we have investigated the proximal promoter regions from both pfmdr1 and pfcrt and identified a number of putative binding sites for nuclear receptors with sequence similarities to regions known to be activated by PB in mammals. Whole-genome analysis has revealed a putative nuclear receptor gene, providing the first evidence that nuclear receptor-mediated responses to drug exposure may be a mechanism of gene regulation in P. falciparum.

* Corresponding author. Mailing address: Molecular and Biochemical Parasitology, Liverpool School of Tropical Medicine, Pembroke Place, Liverpool, Merseyside L3 5QA, United Kingdom. Phone: 44-151-705-3151. Fax: 44-151-705-3371. E-mail: david.johnson{at}liv.ac.uk

{triangledown} Published ahead of print on 14 January 2008.

Antimicrobial Agents and Chemotherapy, April 2008, p. 1438-1445, Vol. 52, No. 4
0066-4804/08/$08.00+0     doi:10.1128/AAC.01392-07
Copyright © 2008, American Society for Microbiology. All Rights Reserved.





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