Skip to main content
Key Specialties
Cardiology Diabetology Endocrinology Gastroenterology Geriatrics and Gerontology Gynecology and Obstetrics Hematology Infectious Disease Internal Medicine Nephrology Neurology Oncology Pediatrics Respiratory Medicine Rheumatology Surgery
Congress Coverage
2024 ACC Congress 2023 ESMO Congress 2023 EASD Congress 2023 ERS Congress 2023 ESC Congress
Clinical Collections
Advances in Alzheimer’s

Keynote webinar | Spotlight on medication adherence

LIVE: Thursday 27th June 2024, 18:00-19:30 (CEST)
Join our expert panel to discover why you need to understand the drivers of non-adherence in your patients, and how you can optimize medication adherence in your clinics to drastically improve patient outcomes.
ADVANCED SEARCH
Log in
Top
Malaria Journal
Published in: Malaria Journal 1/2006

Open Access 01-12-2006 | Research

Assessment of Plasmodium falciparum resistance to ferroquine (SSR97193) in field isolates and in W2 strain under pressure

Authors: Wassim Daher, Christophe Biot, Thierry Fandeur, Helene Jouin, Lydie Pelinski, Eric Viscogliosi, Laurent Fraisse, Bruno Pradines, Jacques Brocard, Jamal Khalife, Daniel Dive

Published in: Malaria Journal | Issue 1/2006

Login to get access

Abstract

Background

Ferroquine (FQ), or SSR97193, is a novel antimalarial drug currently in phase I clinical trials. FQ is a unique organometallic compound designed to overcome the chloroquine (CQ) resistance problem. FQ revealed to be equally active on CQ-sensitive and CQ-resistant Plasmodium falciparum laboratory strains and field isolates. FQ is also curative on rodent malaria parasites. As FQ will be tested in patients, the potential for resistance to this drug was evaluated.

Methods

The relationship between CQ-resistant transporter gene genotype and susceptibility to FQ were studied in 33 Cambodian P. falciparum field isolates previously studied for their in vitro response to CQ. In parallel, the ability of the CQ-resistant strain W2, to become resistant to FQ under drug pressure was assessed.

Results

The IC50 values for FQ in field isolates were found to be unrelated to mutations occurring in the P. falciparum chloroquine resistance transporter (PfCRT) or to the level of expression of the corresponding mRNA. In vitro, under a drug pressure of 100 nM of FQ, transient survival was observed in only one of two experiments.

Conclusion

Field isolates studies and experimental drug pressure experiments showed that FQ overcomes CQ resistance, which reinforces the potential of this compound as a new antimalarial drug.
Appendix
Available only for authorised users
Literature
1.
Egan TJ, Combrinck JM, Egan J, Hearne GR, Marques HM, Ntenteni S, Sewell BT, Smith PJ, Taylor D, van Schalkwyk DA, Walden JC: Fate of haem iron in the malaria parasite Plasmodium falciparum. Biochem J. 2002, 365: 343-347. 10.1042/BJ20020793.PubMedCentralCrossRefPubMed
2.
Ginsburg H, Ward SA, Bray PG: An integrated model of chloroquine action. Parasitol Today. 1999, 15: 357-360. 10.1016/S0169-4758(99)01502-1.CrossRefPubMed
3.
Sanchez CP, Stein W, Lanzer M: Trans stimulation provides evidence for a drug efflux carrier as the mechanism of chloroquine resistance in Plasmodium falciparum. Biochemistry. 2003, 42: 9383-9394. 10.1021/bi034269h.CrossRefPubMed
4.
Fidock DA, Nomura T, Talley AK, Cooper RA, Dzekunov SM, Ferdig MT, Ursos LM, Sidhu AB, Naude B, Deitsch KW, Su XZ, Wootton JC, Roepe PD, Wellems TE: Mutations in the P. falciparum digestive vacuole transmembrane protein PfCRT and evidence for their role in chloroquine resistance. Mol Cell. 2000, 6: 861-871. 10.1016/S1097-2765(05)00077-8.PubMedCentralCrossRefPubMed
5.
Djimde A, Doumbo OK, Cortese JF, Kayentao K, Doumbo S, Diourte Y, Dicko A, Su XZ, Nomura T, Fidock DA, Wellems TE, Plowe CV, Coulibaly D: A molecular marker for chloroquine-resistant falciparum malaria. N Engl J Med. 2001, 344: 257-263. 10.1056/NEJM200101253440403.CrossRefPubMed
6.
Howard EM, Zhang H, Roepe PD: A novel transporter, Pfcrt, confers antimalarial drug resistance. J Membr Biol. 2002, 190: 1-8. 10.1007/s00232-002-1019-3.CrossRefPubMed
7.
Wellems TE: Plasmodium chloroquine resistance and the search for a replacement antimalarial drug. Science. 2002, 298: 124-126. 10.1126/science.1078167.CrossRefPubMed
8.
Waller KL, Muhle RA, Ursos LM, Horrocks P, Verdier-Pinard D, Sidhu AB, Fujioka H, Roepe PD, Fidock DA: Chloroquine resistance modulated in vitro by expression levels of the Plasmodium falciparum chloroquine resistance transporter. J Biol Chem. 2003, 278: 33593-33601. 10.1074/jbc.M302215200.CrossRefPubMed
9.
Biot C, Glorian G, Maciejewski LA, Brocard JS: Synthesis and antimalarial activity in vitro and in vivo of a new ferrocene-chloroquine analogue. J Med Chem. 1997, 40: 3715-3718. 10.1021/jm970401y.CrossRefPubMed
10.
Biot C: Ferroquine: a new weapon in the fight against malaria. Current Medicinal Chemistry-Anti Infective Agents. 2004, 3: 135-147. 10.2174/1568012043354008.CrossRef
11.
Delhaës L, Abessolo H, Biot C, Deloron P, Karbwang J, Mortuaire M, Maciejewski LA, Camus D, Brocard J, Dive D: Ferrochloroquine, a ferrocenyl analogue of chloroquine, retains a potent activity against resistant Plasmodium falciparum in vitro and P. vinckei in vivo. Parasitol Res. 2001, 87: 239-244. 10.1007/s004360000317.CrossRefPubMed
12.
Delhaes L, Biot C, Berry L, Delcourt P, Maciejewski LA, Camus D, Brocard JS, Dive D: Synthesis of ferroquine enantiomers: first investigation of effects of metallocenic chirality upon antimalarial activity and cytotoxicity. Chembiochem. 2002, 3: 418-423. 10.1002/1439-7633(20020503)3:5<418::AID-CBIC418>3.0.CO;2-P.CrossRefPubMed
13.
Atteke C, Ndong JM, Aubouy A, Maciejewski L, Brocard J, Lebibi J, Deloron P: In vitro susceptibility to a new antimalarial organometallic analogue, ferroquine, of Plasmodium falciparum isolates from the Haut-Ogooue region of Gabon. J Antimicrob Chemother. 2003, 51: 1021-1024. 10.1093/jac/dkg161.CrossRefPubMed
14.
Domarle O, Blampain G, Agnaniet H, Nzadiyabi T, Lebibi J, Brocard J, Maciejewski L, Biot C, Georges AJ, Millet P: In vitro antimalarial activity of a new organometallic analog, ferrocene-chloroquine. Antimicrob Agents Chemother. 1998, 42: 540-544.PubMedCentralPubMed
15.
Pradines B, Fusai T, Daries W, Laloge V, Rogier C, Millet P, Panconi E, Kombila M, Parzy D: Ferrocene-chloroquine analogues as antimalarial agents: in vitro activity of ferrochloroquine against 103 Gabonese isolates of Plasmodium falciparum. J Antimicrob Chemother. 2001, 48: 179-184. 10.1093/jac/48.2.179.CrossRefPubMed
16.
Pradines B, Tall A, Rogier C, Spiegel A, Mosnier J, Marrama L, Fusai T, Millet P, Panconi E, Trape JF, Parzy D: In vitro activities of ferrochloroquine against 55 Senegalese isolates of Plasmodium falciparum in comparison with those of standard antimalarial drugs. Trop Med Int Health. 2002, 7: 265-270. 10.1046/j.1365-3156.2002.00848.x.CrossRefPubMed
17.
Chim P, Lim P, Sem R, Nhem S, Maciejewski L, Fandeur T: The in-vitro antimalarial activity of ferrochloroquine, measured against Cambodian isolates of Plasmodium falciparum. Ann Trop Med Parasitol. 2004, 98: 419-424. 10.1179/000349804225003361.CrossRefPubMed
18.
Durrand V, Berry A, Sem R, Glaziou P, Beaudou J, Fandeur T: Variations in the sequence and expression of the Plasmodium falciparum chloroquine resistance transporter (Pfcrt) and their relationship to chloroquine resistance in vitro. Mol Biochem Parasitol. 2004, 136: 273-285. 10.1016/j.molbiopara.2004.03.016.CrossRefPubMed
19.
Rathod PK, McErlean T, Lee PC: Variations in frequencies of drug resistance in Plasmodium falciparum. Proc Natl Acad Sci U S A. 1997, 94: 9389-9393. 10.1073/pnas.94.17.9389.PubMedCentralCrossRefPubMed
20.
Gassis S, Rathod PK: Frequency of drug resistance in Plasmodium falciparum: a nonsynergistic combination of 5-fluoroorotate and atovaquone suppresses in vitro resistance. Antimicrob Agents Chemother. 1996, 40: 914-919.PubMedCentralPubMed
21.
Cooper RA, Ferdig MT, Su XZ, Ursos LM, Mu J, Nomura T, Fujioka H, Fidock DA, Roepe PD, Wellems TE: Alternative mutations at position 76 of the vacuolar transmembrane protein PfCRT are associated with chloroquine resistance and unique stereospecific quinine and quinidine responses in Plasmodium falciparum. Mol Pharmacol. 2002, 61: 35-42. 10.1124/mol.61.1.35.CrossRefPubMed
22.
23.
Desjardins RE, Canfield CJ, Haynes JD, Chulay JD: Quantitative assessment of antimalarial activity in vitro by a semiautomated microdilution technique. Antimicrob Agents Chemother. 1979, 16: 710-718.PubMedCentralCrossRefPubMed
24.
Millet J, Alibert S, Torrentino-Madamet M, Rogier C, Santelli-Rouvier C, Bigot P, Mosnier J, Baret E, Barbe J, Parzy D, Pradines B: Polymorphism in Plasmodium falciparum drug transporter proteins and reversal of in vitro chloroquine resistance by a 9, 10-dihydroethanoanthracene derivative. Antimicrob Agents Chemother. 2004, 48: 4869-4872. 10.1128/AAC.48.12.4869-4872.2004.PubMedCentralCrossRefPubMed
25.
26.
Huelsenbeck JP, Ronquist F: MRBAYES: Bayesian inference of phylogenetic trees. Bioinformatics. 2001, 17: 754-755. 10.1093/bioinformatics/17.8.754.CrossRefPubMed
27.
Jones DT, Taylor WR, Thornton JM: The rapid generation of mutation data matrices from protein sequences. Comput Appl Biosci. 1992, 8: 275-282.PubMed
28.
Green PJ: Reversible jump Markov chain Monte Carlo computation and Bayesian model determination. Biometrika. 1995, 82: 711-732.CrossRef
29.
Jouin H, Daher W, Khalife J, Ricard I, Puijalon OM, Capron M, Dive D: Double staining of Plasmodium falciparum nucleic acids with hydroethidine and thiazole orange for cell cycle stage analysis by flow cytometry. Cytometry A. 2004, 57: 34-38. 10.1002/cyto.a.10110.CrossRefPubMed
30.
Martin RE, Kirk K: The malaria parasite's chloroquine resistance transporter is a member of the drug/metabolite transporter superfamily. Mol Biol Evol. 2004, 21: 1938-1949. 10.1093/molbev/msh205.CrossRefPubMed
31.
Warhurst DC: Polymorphism in the Plasmodium falciparum chloroquine-resistance transporter protein links verapamil enhancement of chloroquine sensitivity with the clinical efficacy of amodiaquine. Malar J. 2003, 2: 31-43. 10.1186/1475-2875-2-31.PubMedCentralCrossRefPubMed
32.
Walliker D, Hunt P, Babiker H: Fitness of drug-resistant malaria parasites. Acta Trop. 2005, 94: 251-259.CrossRefPubMed
33.
Hastings IM, Donnelly MJ: The impact of antimalarial drug resistance mutations on parasite fitness, and its implications for the evolution of resistance. Drug Resist Updat. 2005, 8: 43-50. 10.1016/j.drup.2005.03.003.CrossRefPubMed
34.
Hayward R, Saliba KJ, Kirk K: pfmdr1 mutations associated with chloroquine resistance incur a fitness cost in Plasmodium falciparum. Mol Microbiol. 2005, 55: 1285-1295. 10.1111/j.1365-2958.2004.04470.x.CrossRefPubMed
35.
Paget-McNicol S, Saul A: Mutation rates in the dihydrofolate reductase gene of Plasmodium falciparum. Parasitology. 2001, 122: 497-505. 10.1017/S0031182001007739.CrossRefPubMed
36.
Anderson TJ, Roper C: The origins and spread of antimalarial drug resistance: lessons for policy makers. Acta Trop. 2005, 94: 269-280.CrossRefPubMed
37.
Price RN, Uhlemann AC, Brockman A, McGready R, Ashley E, Phaipun L, Patel R, Laing K, Looareesuwan S, White NJ, Nosten F, Krishna S: Mefloquine resistance in Plasmodium falciparum and increased pfmdr1 gene copy number. Lancet. 2004, 364: 438-447. 10.1016/S0140-6736(04)16767-6.PubMedCentralCrossRefPubMed
38.
Klokouzas A, Shahi S, Hladky SB, Barrand MA, van Veen HW: ABC transporters and drug resistance in parasitic protozoa. Int J Antimicrob Agents. 2003, 22: 301-317. 10.1016/S0924-8579(03)00210-3.CrossRefPubMed
39.
Mu J, Ferdig MT, Feng X, Joy DA, Duan J, Furuya T, Subramanian G, Aravind L, Cooper RA, Wootton JC, Xiong M, Su XZ: Multiple transporters associated with malaria parasite responses to chloroquine and quinine. Mol Microbiol. 2003, 49: 977-989. 10.1046/j.1365-2958.2003.03627.x.CrossRefPubMed
40.
Ferdig MT, Cooper RA, Mu J, Deng B, Joy DA, Su XZ, Wellems TE: Dissecting the loci of low-level quinine resistance in malaria parasites. Mol Microbiol. 2004, 52: 985-997. 10.1111/j.1365-2958.2004.04035.x.CrossRefPubMed
41.
Trotta RF, Brown ML, Terrell JC, Geyer JA: Defective DNA repair as a potential mechanism for the rapid development of drug resistance in Plasmodium falciparum. Biochemistry. 2004, 43: 4885-4891. 10.1021/bi0499258.CrossRefPubMed
Metadata
Title
Assessment of Plasmodium falciparum resistance to ferroquine (SSR97193) in field isolates and in W2 strain under pressure
Authors
Wassim Daher
Christophe Biot
Thierry Fandeur
Helene Jouin
Lydie Pelinski
Eric Viscogliosi
Laurent Fraisse
Bruno Pradines
Jacques Brocard
Jamal Khalife
Daniel Dive
Publication date
01-12-2006
Publisher
BioMed Central
Published in
Malaria Journal / Issue 1/2006
Electronic ISSN: 1475-2875
DOI
https://doi.org/10.1186/1475-2875-5-11

Other articles of this Issue 1/2006

Malaria Journal 1/2006 Go to the issue

Research

Landscape determinants and remote sensing of anopheline mosquito larval habitats in the western Kenya highlands

Research

Water quality and immatures of the M and S forms of Anopheles gambiae s.s. and An. arabiensis in a Malian village

Case study

Over-diagnosis of malaria is not a lost cause

Review

Costing the distribution of insecticide-treated nets: a review of cost and cost-effectiveness studies to provide guidance on standardization of costing methodology

Research

Status of insecticide susceptibility in Anopheles arabiensis from Mwea rice irrigation scheme, Central Kenya

Methodology

Production and validation of durable, high quality standardized malaria microscopy slides for teaching, testing and quality assurance during an era of declining diagnostic proficiency
Live Webinar | 27-06-2024 | 18:00 (CEST)

Keynote webinar | Spotlight on medication adherence

Reserve your place

Live: Thursday 27th June 2024, 18:00-19:30 (CEST)

WHO estimates that half of all patients worldwide are non-adherent to their prescribed medication. The consequences of poor adherence can be catastrophic, on both the individual and population level.

Join our expert panel to discover why you need to understand the drivers of non-adherence in your patients, and how you can optimize medication adherence in your clinics to drastically improve patient outcomes.

Prof. Kevin Dolgin
Prof. Florian Limbourg
Prof. Anoop Chauhan
Developed by: Springer Medicine
Obesity Clinical Trial Summary

At a glance: The STEP trials

Read more

A round-up of the STEP phase 3 clinical trials evaluating semaglutide for weight loss in people with overweight or obesity.

Developed by: Springer Medicine

Highlights from the ACC 2024 Congress

Year in Review: Pediatric cardiology

Pediatric Cardiology Video

Watch Dr. Anne Marie Valente present the last year's highlights in pediatric and congenital heart disease in the official ACC.24 Year in Review session.

Year in Review: Pulmonary vascular disease

Cardiopulmonary Comorbidity Video

The last year's highlights in pulmonary vascular disease are presented by Dr. Jane Leopold in this official video from ACC.24.

Year in Review: Valvular heart disease

Valvular Heart Disease Video

Watch Prof. William Zoghbi present the last year's highlights in valvular heart disease from the official ACC.24 Year in Review session.

Year in Review: Heart failure and cardiomyopathies

Heart Failure Video

Watch this official video from ACC.24. Dr. Biykem Bozkurt discusses last year's major advances in heart failure and cardiomyopathies.

ACC 2024 Congress Coverage

Year in Review: Heart failure and cardiomyopathies

Heart Failure Video

Watch this official video from ACC.24. Dr. Biykem Bozkurt discusses last year's major advances in heart failure and cardiomyopathies.

Watch now

Semaglutide benefits people with type 2 diabetes and obesity-related heart failure

16-04-2024 Type 2 Diabetes News

Incentivised to exercise

11-04-2024 Lifestyle Modifications News

New intervention for STEMI-related cardiogenic shock

10-04-2024 Myocardial Infarction News

» View more highlights on the ACC 2024 congress hub page

Image Credits