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Antimicrobial Agents and Chemotherapy, November 2008, p. 4030-4036, Vol. 52, No. 11
0066-4804/08/$08.00+0     doi:10.1128/AAC.00964-08
Copyright © 2008, American Society for Microbiology. All Rights Reserved.

Sitamaquine Sensitivity in Leishmania Species Is Not Mediated by Drug Accumulation in Acidocalcisomes{triangledown}

Carmen López-Martín, José María Pérez-Victoria, Luis Carvalho, Santiago Castanys,* and Francisco Gamarro*

Instituto de Parasitología y Biomedicina López-Neyra, CSIC, Parque Tecnológico de Ciencias de la Salud, Avda. del Conocimiento s/n, 18100 Armilla, Granada, Spain

Received 21 July 2008/ Returned for modification 18 August 2008/ Accepted 5 September 2008

Sitamaquine (WR6026), an 8-aminoquinoline derivative, is a new antileishmanial oral drug. As a lipophilic weak base, it rapidly accumulates in acidic compartments, represented mainly by acidocalcisomes. In this work, we show that the antileishmanial action of sitamaquine is unrelated to its level of accumulation in these acidic vesicles. We have observed significant differences in sitamaquine sensitivity and accumulation between Leishmania species and strains, and interestingly, there is no correlation between them. However, there is a relationship between the levels of accumulation of sitamaquine and acidotropic probes, acidocalcisomes size, and polyphosphate levels. The Leishmania major AP3{delta}-null mutant line, in which acidocalcisomes are devoid of their usual polyphosphate and proton content, is unable to accumulate sitamaquine; however, both the parental strain and the AP3{delta}-null mutants showed similar sensitivities to sitamaquine. Our findings provide clear evidence that the antileishmanial action of sitamaquine is unrelated to its accumulation in acidocalcisomes.

* Corresponding author. Mailing address: Instituto de Parasitología y Biomedicina López-Neyra, CSIC, Parque Tecnológico de Ciencias de la Salud, Avda. del Conocimiento s/n, 18100 Armilla, Granada, Spain. Phone for Francisco Gamarro: 34 958 181667. Fax: 34 958 181632. E-mail: gamarro{at}ipb.csic.es. Phone for Santiago Castanys: 34 958 181666. Fax: 34 958 181632. E-mail: castanys{at}ipb.csic.es

{triangledown} Published ahead of print on 15 September 2008.

Antimicrobial Agents and Chemotherapy, November 2008, p. 4030-4036, Vol. 52, No. 11
0066-4804/08/$08.00+0     doi:10.1128/AAC.00964-08
Copyright © 2008, American Society for Microbiology. All Rights Reserved.





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