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Malaria Journal
Published in: Malaria Journal 1/2010

Open Access 01-12-2010 | Research

Suppressive effect of azithromycin on Plasmodium berghei mosquito stage development and apicoplast replication

Authors: Shoichi Shimizu, Yoshio Osada, Tamotsu Kanazawa, Yoshiya Tanaka, Meiji Arai

Published in: Malaria Journal | Issue 1/2010

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Abstract

Background

Azithromycin (AZM) is a macrolide antibiotic that displays an excellent safety profile even in children and pregnant women and has been shown to have anti-malarial activity against blood stage Plasmodium falciparum. This study evaluated the transmission-blocking effect of AZM using a rodent malaria model.

Methods

AZM-treated mice infected with Plasmodium berghei were exposed to Anopheles stephensi mosquitoes, followed by the observation of parasite development at different phases in the mosquito, i.e., ookinetes in the midgut, oocysts on the midgut, and sporozoites in the midgut and salivary glands. Furthermore, to evaluate the effect on organelle replication of each stage, quantitative real-time PCR analysis was performed.

Results

The inhibitory effect of AZM was noticeable in both gametocyte-ookinete transformation in the midgut and sporozoite production in the oocyst, while the latter was most remarkable among all the developmental phases examined. Real-time PCR analysis revealed that AZM suppressed apicoplast replication at the period of sporozoite production in oocysts.

Conclusions

AZM inhibits parasite development in the mosquito stage, probably through the same mechanism as in the liver and blood stages. Such a multi-targeting anti-malarial, along with its safety, would be ideal for mass drug administration in malaria control programmes.
Appendix
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Literature
1.
Aregawi M, Cibulskis R, Otten M, Williams R, Dye C: World Malaria Report 2008. 2008, World Health Organization, Geneva
2.
Carter R, Mendis KN, Miller LH, Molineaux L, Saul A: Malaria transmission-blocking vaccines--how can their development be supported?. Nat Med. 2000, 6: 241-244. 10.1038/73062.CrossRefPubMed
3.
Kaslow DC: Transmission-blocking vaccines: Uses and current status of development. Int J Parasitol. 1997, 27: 183-189. 10.1016/S0020-7519(96)00148-8.CrossRefPubMed
4.
Bucher GA: Antimalarial drugs and the mosquito transmission of Plasmodium. Int J Parasitol. 1997, 27: 975-987. 10.1016/S0020-7519(97)00079-9.CrossRef
5.
Coleman RE, Nath AK, Schneider I, Song GH, Klein TA, Milhous WK: Prevention of sporogony of Plasmodium falciparum and P. berghei in Anopheles stephensi mosquitoes by transmission-blocking antimalarials. Am J Trop Med Hyg. 1994, 50: 646-653.PubMed
6.
De Martin S, von Seidlein L, Deen JL, Pinder M, Walraven G, Greenwood BM: Community perceptions of a mass administration of an antimalarial drug combination in The Gambia. Trop Med Int Health. 2001, 6: 442-448. 10.1046/j.1365-3156.2001.00723.x.CrossRefPubMed
7.
von Seidlein L, Greenwood BM: Mass drug administration of antimalarial drugs. Trends Parasitol. 2003, 10: 452-460. 10.1016/j.pt.2003.08.003.CrossRef
8.
9.
Doi H, Kaneko A, Panjaitan W, Ishii A: Chemotherapeutic malaria control operation by single dose or Fansidar plus primaquine in North Sumatra, Indonesia. Southeast Asian J Trop Med Public Health. 1989, 20: 341-349.PubMed
10.
Kaneko A, Taleo G, Kalkoa M, Yamar S, Kobayakawa T, Björkman A: Malaria eradication on islands. Lancet. 2000, 356: 1560-1564. 10.1016/S0140-6736(00)03127-5.CrossRefPubMed
11.
Chotivanich K, Sattabongkot J, Udomsangpetch R, Looareesuwan S, Day NPJ, Coleman RE, White NJ: Transmission-blocking activities of quinine, primaquine, and artesunate. Antimicrob Agents Chemother. 2006, 50: 1927-1930. 10.1128/AAC.01472-05.PubMedCentralCrossRefPubMed
12.
Coleman RE, Polsa N, Eikarat N, Kollars TM, Sattabongkot J: Prevention of sporogony of Plasmodium vivax in Anopheles dirus mosquitoes by transmission-blocking antimalarials. Am J Trop Med Hyg. 2001, 65: 214-218.PubMed
13.
Pukrittayakamee S, Chotivanich K, Chantra A, Clemens R, Looareesuwan S, White NJ: Activities of artesunate and primaquine against asexual- and sexual-stage parasites in falciparum malaria. Antimicrob Agents Chemother. 2004, 48: 1329-1334. 10.1128/AAC.48.4.1329-1334.2004.PubMedCentralCrossRefPubMed
14.
Arai M, Alavi YIH, Mendoza J, Billker O, Sinden RE: Isonicotinic acid hydrazide: an anti-tuberculosis drug inhibits malarial transmission in the mosquito gut. Exp Parasitol. 2004, 106: 30-36. 10.1016/j.exppara.2004.01.002.CrossRefPubMed
15.
Sidhu AB, Sun Q, Nkrumah LJ, Dunne MW, Sacchettini JC, Fidock DA: In vitro efficacy, resistance selection, and structural modeling studies implicate the malarial parasite apicoplast as the target of azithromycin. J Biol Chem. 2007, 282: 2494-2504. 10.1074/jbc.M608615200.CrossRefPubMed
16.
Sarkar M, Woodland C, Koren G, Einarson AR: Pregnancy outcome following gestational exposure to azithromycin. BMC Pregnancy Childbirth. 2006, 6: 18-10.1186/1471-2393-6-18.PubMedCentralCrossRefPubMed
17.
Treadway G, Pontani D: Paediatric safety of azithromycin: worldwide experience. J Antimicrob Chemother. 1996, 37 (Suppl C): 143-149.CrossRefPubMed
18.
Andersen SL, Ager AL, McGreevy P, Schuster BG, Ellis W, Berman J: Efficacy of azithromycin as a causal prophylactic agent against murine malaria. Antimicrob Agents Chemother. 1994, 38: 1862-1863.PubMedCentralCrossRefPubMed
19.
Gingras BA, Jensen JB: Antimalarial activity of azithromycin and erythromycin against Plasmodium berghei. Am J Trop Med Hyg. 1993, 49: 101-105.PubMed
20.
Noedl H, Krudsood S, Leowattana W, Tangpukdee N, Thanachartwet W, Looareesuwan S, Miller RS, Fukuda M, Jongsakul K, Yingyuen K, Sriwichai S, Ohrt C, Knirsch C: In vitro antimalarial activity of azithromycin, artesunate, and quinine in combination and correlation with clinical outcome. Antimicrob Agents Chemother. 2007, 51: 651-656. 10.1128/AAC.01023-06.PubMedCentralCrossRefPubMed
21.
Chico RM, Pittrof R, Greenwood B, Chandramohan D: Azithromycin-chloroquine and the intermittent preventive treatment of malaria in pregnancy. Malar J. 2008, 7: 255-10.1186/1475-2875-7-255.PubMedCentralCrossRefPubMed
22.
Noedl H, Krudsood S, Chalermratana K, Silachamroon U, Leowattana W, Tangpukdee N, Looareesuwan S, Miller RS, Fukuda M, Jongsakul K, Sriwichai S, Rowan J, Bhattacharyya H, Ohrt C, Knirsch C: Azithromycin combination therapy with artesunate or quinine for the treatment of uncomplicated Plasmodium falciparum malaria in adults: a randomized, phase 2 clinical trial in Thailand. Clin Infect Dis. 2006, 43: 1264-1271. 10.1086/508175.CrossRefPubMed
23.
Dunne MW, Singh N, Shukla M, Valecha N, Bhattacharyya PC, Patel K, Mohapatra MK, Lakhani J, Devi CU, Adak T, Dev V, Yadav RS, Lele C, Patki K: A double-blind, randomized study of azithromycin compared to chloroquine for the treatment of Plasmodium vivax malaria in India. Am J Trop Med Hyg. 2005, 73: 1108-1111.PubMed
24.
Dahl EL, Rosenthal PJ: Multiple antibiotics exert delayed effects against the Plasmodium falciparum apicoplast. Antimicrob Agents Chemother. 2007, 51: 3485-3490. 10.1128/AAC.00527-07.PubMedCentralCrossRefPubMed
25.
26.
van Dijk MR, Janse CJ, Thompson J, Waters AP, Braks JA, Dodemont HJ, Stunnenberg HG, van Gemert GJ, Sauerwein RW, Eling W: A central role for P48/45 in malaria parasite male gamete fertility. Cell. 2001, 104: 153-164. 10.1016/S0092-8674(01)00199-4.CrossRefPubMed
27.
Talman AM, Domarle O, McKenzie FE, Ariey F, Robert V: Gametocytogenesis: the puberty of Plasmodium falciparum. Malar J. 2004, 3: 24-10.1186/1475-2875-3-24.PubMedCentralCrossRefPubMed
28.
Arai M, Billker O, Morris HR, Panico M, Delcroix M, Dixon D, Ley SV, Sinden RE: Both mosquito-derived xanthurenic acid and a host blood-derived factor regulate gametogenesis of Plasmodium in the midgut of the mosquito. Mol Biochem Parasitol. 2001, 116: 17-24. 10.1016/S0166-6851(01)00299-7.CrossRefPubMed
29.
Vaidya AB, Mather MW: Mitochondrial evolution and functions in malaria parasites. Annu Rev Microbiol. 2009, 63: 249-267. 10.1146/annurev.micro.091208.073424.CrossRefPubMed
30.
31.
Ramya TN, Mishra S, Karmodiya K, Surolia N, Surolia A: Inhibitors of nonhousekeeping functions of the apicoplast defy delayed death in Plasmodium falciparum. Antimicrob Agents Chemother. 2007, 51: 307-316. 10.1128/AAC.00808-06.PubMedCentralCrossRefPubMed
32.
Ramya TN, Karmodiya K, Surolia A, Surolia N: 15-deoxyspergualin primarily targets the trafficking of apicoplast proteins in Plasmodium falciparum. J Biol Chem. 2007, 282: 6388-6397. 10.1074/jbc.M610251200.CrossRefPubMed
33.
Stanway RR, Witt T, Zobiak B, Aepfelbacher M, Heussler VT: GFP-targeting allows visualization of the apicoplast throughout the life cycle of live malaria parasites. Biol Cell. 2009, 101: 415-430. 10.1042/BC20080202.CrossRefPubMed
34.
Dunne MW, Singh N, Shukla M, Valecha N, Bhattacharyya PC, Dev V, Patel K, Mohapatra MK, Lakhani J, Benner R, Lele C, Patki K: A multicenter study of azithromycin, alone and in combination with chloroquine, for the treatment of acute uncomplicated Plasmodium falciparum malaria in India. J Infect Dis. 2005, 191: 1582-1588. 10.1086/429343.CrossRefPubMed
35.
Miller RS, Wongsrichanalai C, Buathong N, McDaniel P, Walsh DS, Knirsch C, Ohrt C: Effective treatment of uncomplicated Plasmodium falciparum malaria with azithromycin-quinine combinations: a randomized, dose-ranging study. Am J Trop Med Hyg. 2006, 74: 401-406.PubMed
36.
Creasey A, Mendis K, Carlton J, Williamson D, Wilson I, Carter R: Maternal inheritance of extrachromosomal DNA in malaria parasites. Mol Biochem Parasitol. 1994, 65: 95-98. 10.1016/0166-6851(94)90118-X.CrossRefPubMed
37.
Okamoto N, Spurck TP, Goodman CD, McFadden GI: Apicoplast and mitochondrion in gametocytogenesis of Plasmodium falciparum. Eukaryot Cell. 2009, 8: 128-132. 10.1128/EC.00267-08.PubMedCentralCrossRefPubMed
38.
van Dooren GG, Marti M, Tonkin CJ, Stimmler LM, Cowman AF, McFadden GI: Development of the endoplasmic reticulum, mitochondrion and apicoplast during the asexual life cycle of Plasmodium falciparum. Mol Microbiol. 2006, 57: 405-419. 10.1111/j.1365-2958.2005.04699.x.CrossRef
39.
Landau I, Boulard Y: Life cycles and morphology. Rodent Malaria. Edited by: Killick-Kenckrick R, Peters W. 1978, New York: Academic Press, 53-84.
40.
Sinden RE, Dawes EJ, Alavi Y, Waldock J, Finney O, Mendoza J, Butcher GA, Andrews L, Hill AV, Gilbert SC, Basanez MG: Progression of Plasmodium berghei through Anopheles stephensi is density-dependent. PLoS Pathog. 2007, 3: e195-10.1371/journal.ppat.0030195.PubMedCentralCrossRefPubMed
41.
Pukrittayakamee S, Imwong M, Singhasivanon P, Stepniewska K, Day NJ, White NJ: Effects of different antimalarial drugs on gametocyte carriage in P. vivax malaria. Am J Trop Med Hyg. 2008, 79: 378-384.PubMed
42.
Rino BE, Van TT, Giovanni F, Franco M: Azithromycin in the treatment of Plasmodium falciparum gametocytes: a preliminary observation. J Trop Pediatr. 2000, 46: 56-10.1093/tropej/46.1.56.CrossRefPubMed
43.
Medley GF, Sinden RE, Fleck S, Billingsley PF, Tirawanchai N, Rodriguez MH: Heterogeneity in patterns of malarial oocyst infections in the mosquito vector. Parasitology. 1993, 106: 441-449. 10.1017/S0031182000076721.CrossRefPubMed
44.
Awono-Ambene HP, Diawara L, Robert V: Comparison of direct and membrane feeding methods to infect Anopheles arabiensis with Plasmodium falciparum. Am J Trop Med Hyg J. 2001, 64: 32-34.
45.
Ouédraogo AL, Bousema T, Schneider P, de Vlas SJ, Ilboudo-Sanogo E, Cuzin-Ouattara N, Nébié I, Roeffen W, Verhave JP, Luty AJ, Sauerwein R: Substantial contribution of submicroscopical Plasmodium falciparum gametocyte carriage to the infectious reservoir in an area of seasonal transmission. PLoS One. 2009, 4: e8410-10.1371/journal.pone.0008410.PubMedCentralCrossRefPubMed
46.
Zollner GE, Ponsa N, Garman GW, Poudel S, Bell JA, Sattabongkot J, Coleman RE, Vaughan JA: Population dynamics of sporogony for Plasmodium vivax parasites from western Thailand developing within three species of colonized Anopheles mosquitoes. Malar J. 2006, 5: 68-10.1186/1475-2875-5-68.PubMedCentralCrossRefPubMed
47.
Blasi F, Aliberti S, Tarsia P: Clinical applications of azithromycin microspheres in respiratory tract infections. Int J Nanomedicine. 2007, 2: 551-559.PubMedCentralPubMed
48.
Girard AE, Girard D, English AR, Gootz TD, Cimochowski CR, Faiella JA, Haskell SL, Retsema JA: Pharmacokinetic and in vivo studies with azithromycin (CP-62,993), a new macrolide with an extended half-life and excellent tissue distribution. Antimicrob Agents Chemother. 1987, 31: 1948-1954.PubMedCentralCrossRefPubMed
49.
Luke DR, Foulds G, Cohen SF, Levy B: Safety, toleration, and pharmacokinetics of intravenous azithromycin. Antimicrob Agents Chemother. 1996, 40: 2577-2581.PubMedCentralPubMed
50.
Girard D, Finegan SM, Dunne MW, Lame ME: Enhanced efficacy of single-dose versus multi-dose azithromycin regimens in preclinical infection models. J Antimicrob Chemother. 2005, 56: 365-371. 10.1093/jac/dki241.CrossRefPubMed
Metadata
Title
Suppressive effect of azithromycin on Plasmodium berghei mosquito stage development and apicoplast replication
Authors
Shoichi Shimizu
Yoshio Osada
Tamotsu Kanazawa
Yoshiya Tanaka
Meiji Arai
Publication date
01-12-2010
Publisher
BioMed Central
Published in
Malaria Journal / Issue 1/2010
Electronic ISSN: 1475-2875
DOI
https://doi.org/10.1186/1475-2875-9-73

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