Abstract
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.
Highlights
Leishmaniasis is the medical term used to define an array of diseases caused by pathogenic species of Leishmania parasites
The structure of PAR bound to an RNA duplex representing two Leishmania ribosomal A-sites was elucidated by X-ray crystallography at 3.0Aresolution (Supplementary Table S1, Figure 2)
We further evaluated the compounds potency as possible therapeutic agents for the treatment of leishmaniasis by determining their activity against intracellular L. donovani amastigotes in the infected THP-1 macrophage cell line (Figure 5C)
Summary
Leishmaniasis is the medical term used to define an array of diseases caused by pathogenic species of Leishmania parasites. More than 20 disease-causing parasites have been identified so far, afflicting ∼100 epidemic countries located mainly in tropical, subtropical areas and southern Europe [1]. Leishmania parasites are transmitted to humans by the bite of infected sandflies, causing a variety of symptoms ranging from mild to life-threatening, with the most common forms being cutaneous leishmaniasis (CL), which causes self-healing skin ulcers, and visceral leishmaniasis (VL), which is lethal if untreated [1]. PAR has broad-spectrum antibacterial activities, but due to its strong ability to inhibit protozoan growth it is mainly used orally for the treatment of intestinal parasite infections such as amoebiasis, giardiasis and tapeworm disease [2]
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