Structural basis for selective targeting of leishmanial ribosomes: aminoglycoside derivatives as promising therapeutics.
Leishmaniasis comprises an array of diseases caused by pathogenic species of Leishmania, resulting in a spectrum of mild to life-threatening pathologies. Currently available therapies for leishmaniasis include a limited selection of drugs. This coupled with the rather fast emergence of parasite resistance, presents a dire public health concern. Paromomycin (PAR), a broad-spectrum aminoglycoside antibiotic, has been shown in recent years to be highly efficient in treating visceral leishmaniasis (VL)-the life-threatening form of the disease. While much focus has been given to exploration of PAR activities in bacteria, its mechanism of action in Leishmania has received relatively little scrutiny and has yet to be fully deciphered. In the present study we present an X-ray structure of PAR bound to rRNA model mimicking its leishmanial binding target, the ribosomal A-site. We also evaluate PAR inhibitory actions on leishmanial growth and ribosome function, as well as effects on auditory sensory cells, by comparing several structurally related natural and synthetic aminoglycoside derivatives. The results provide insights into the structural elements important for aminoglycoside inhibitory activities and selectivity for leishmanial cytosolic ribosomes, highlighting a novel synthetic derivative, compound 3: , as a prospective therapeutic candidate for the treatment of VL.
Schulich Faculty of Chemistry, Technion-Israel Institute of Technology, Haifa, Israel Department of Structural Biology, Faculty of Chemistry, Weizmann Institute of Science, Rehovot, Israel.
Moran
M
Shalev
Department of Structural Biology, Faculty of Chemistry, Weizmann Institute of Science, Rehovot, Israel.
Haim
H
Rozenberg
Schulich Faculty of Chemistry, Technion-Israel Institute of Technology, Haifa, Israel.
Boris
B
Smolkin
Department of Microbiology and Molecular Genetics, IMRIC, Hebrew University-Hadassah Medical School, Jerusalem, Israel.
Abedelmajeed
A
Nasereddin
Department of Microbiology and Molecular Genetics, IMRIC, Hebrew University-Hadassah Medical School, Jerusalem, Israel.
Dmitry
D
Kopelyanskiy
Schulich Faculty of Chemistry, Technion-Israel Institute of Technology, Haifa, Israel.
Valery
V
Belakhov
Kresge Hearing Research Institute, Department of Otolaryngology, University of Michigan Medical School, Ann Arbor, Michigan, USA.
Thomas
T
Schrepfer
Kresge Hearing Research Institute, Department of Otolaryngology, University of Michigan Medical School, Ann Arbor, Michigan, USA.
Jochen
J
Schacht
Department of Microbiology and Molecular Genetics, IMRIC, Hebrew University-Hadassah Medical School, Jerusalem, Israel.
Charles L
CL
Jaffe
Schulich Faculty of Chemistry, Technion-Israel Institute of Technology, Haifa, Israel.
Noam
N
Adir
Schulich Faculty of Chemistry, Technion-Israel Institute of Technology, Haifa, Israel chtimor@techunix.technion.ac.il.
Timor
T
Baasov
D000818:Animals; D000981:Antiprotozoal Agents / Q000737:chemistry* / Q000494:pharmacology / Q000633:toxicity; D001665:Binding Sites; D002460:Cell Line; D003198:Computer Simulation; D006168:Guinea Pigs; D006801:Humans; D007891:Leishmania / Q000187:drug effects* / Q000254:growth & development; D008264:Macrophages / Q000469:parasitology; D008297:Male; D008958:Models, Molecular; D009355:Neomycin / Q000031:analogs & derivatives / Q000737:chemistry / Q000633:toxicity; D010303:Paromomycin / Q000737:chemistry* / Q000494:pharmacology / Q000633:toxicity; D014176:Protein Biosynthesis / Q000187:drug effects; D011500:Protein Synthesis Inhibitors / Q000737:chemistry* / Q000494:pharmacology / Q000633:toxicity; D012335:RNA, Ribosomal / Q000737:chemistry; D012270:Ribosomes / Q000737:chemistry / Q000187:drug effects*
D000981:Antiprotozoal Agents; D011500:Protein Synthesis Inhibitors; D012335:RNA, Ribosomal; D010303:Paromomycin; D009355:Neomycin