Differential effects of paramomycin on ribosomes of Leishmania mexicana and mammalian cells.

FERNÁNDEZ MM; MALCHIODI EL; ALGARNATI ID

ANTIMICROBIAL AGENTS AND CHEMOTHERAPY

AMER SOC MICROBIOLOGY

Año: 2011 vol. 55 p. 86 - 93

0066-4804

Paromomycin, an aminoglycoside antibiotic of low toxicity for mammalian cells, is one of the drugs currently used in the chemotherapy of cutaneous and visceral leishmaniasis. In order to understand the mode of action of this antibiotic at the molecular level we have investigated the effects of paromomycin on protein synthesis in Leishmania and its mammalian hosts. We have been able to demonstrate that in vivo protein synthesis in the parasite and its proliferation rate are markedly inhibited by paromomycin, while they are only slightly affected by other aminoglycoside antibiotics such as streptomycin and neomycin B. Furthermore, both the in vitro polypeptide synthesis induced by poly U as messenger RNA as well as the accuracy of translation are significantly decreased by paromomycin in cell-free systems containing ribosomal particles from Leishmania. Conversely, when ribosomes from mammalian cells are used instead of the protozoan particles, polyphenylalanine synthesis is only barely reduced by the antibiotic and the translation misreading remain almost unaltered. Surface plasmon resonance analysis of the interaction between paromomycin and protozoan or mammalian cell ribosomal RNAs show a strong binding of the antibiotic to the parasite ribosomal decoding site and practically no interaction with the mammalian cell counterpart. Our results indicating differential effects of paromomycin on the translation processes of Leishmania and its mammalian hosts can explain the therapeutic efficiency of the antibiotic as an antileishmaniasis agent.