Leishmaniasis, a parasitic disease caused by protozoa of the genus Leishmania, affects millions of people worldwide, appearing mainly in tropical and subtropical areas. The disease is transmitted by infected species of sand fly, and can be fatal if untreated. The current state-of-art in treating leishmaniasis is based on combined chemotherapy of limited array of drugs.
Aminoglycosides are mostly known as highly potent, broad-spectrum antibiotics that exert their antibacterial activity by selectively targeting the decoding A-site of the bacterial ribosome, leading to aberrant protein synthesis. Recently, aminoglycosides containing a 6'-OH group were highlighted as excellent candidates for the treatment of leishmaniasis. Nevertheless, although some aminoglycosides have already been clinically approved and are currently used worldwide for the treatment of leishmaniasis, the mechanism of which aminoglycosides induce their deleterious effect on leishmaina is rather obscure. Based on high conservation of aminoglycosides binding site in bacteria among all kingdoms, it is assumed that the putative binding site of these agents in Leishmania is the ribosomal A-site. However, while the recent X-ray crystal structures of the bacterial ribosome in complex with aminoglycosides shed light on the mechanism of aminoglycosides action as antibiotics, no such data is presently available regarding to their putative binding site in leishmania.
Herein we present the crystal structures of two aminoglycosides bound to their leishmanian binding site: G418, a potent aminoglycoside for the treatment of leishmaniasis at a 2.6Å resolution, and Apramycin, a strong binder for the leishmanian ribosome at 1.4Å resolution. The observed data provides the first demonstration of aminoglycosides binding to leishmania ribosomes; therefore illuminates the understanding of aminoglycosides mode of action in leishmania at the molecular level. The observed structural data sets ground for rational design of new derivatives as potential therapeutic agents against leishmaniasis.
