Characterization of a compensatory mutant of Leishmania major that lacks ether lipids but exhibits normal growth, and G418 and hygromycin resistance

Zufferey, Rachel; Bibis, Stergios S.; Zhu, Tongtong; Dhalladoo, Subbhalakshmi

doi:10.1016/j.exppara.2012.01.008

Cited by 3 publications

(2 citation statements)

References 31 publications

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“…All AGs tested inhibited Leishmania growth in a dosedependent manner. The LC 50 values obtained for the 6′-OH AGs (Paromomycin and G418) were in the μM range, and showed good agreement with previous published values for these compounds (18,35,36). The obtained LC 50 values for the 6′-NH 2 derivatives (Neomycin and Gentamicin) were higher than those obtained for the 6′-OH derivatives, and are also in good agreement with previously reported work demonstrating the lower potency of Neomycin B, compared with Paromomycin, for treatment of leishmaniasis (18).…”

Section: In Vitro Inhibition Of Leishmania Donovani and Leishmania Majorsupporting

confidence: 75%

Identification of the molecular attributes required for aminoglycoside activity against Leishmania

Shalev

Kondo

Kopelyanskiy³

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

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Leishmaniasis, a parasitic disease caused by protozoa of the genus Leishmania , affects millions of people worldwide. 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, some aminoglycosides have been clinically approved and are currently used worldwide for the treatment of leishmaniasis; however the molecular details by which aminoglycosides induce their deleterious effect on Leishmaina is still rather obscure. Based on high conservation of the decoding site among all kingdoms, it is assumed that the putative binding site of these agents in Leishmania is the ribosomal A site. However, although 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 are presently available regarding their binding site in Leishmania . We present crystal structures of two different aminoglycoside molecules bound to a model of the Leishmania ribosomal A site: Geneticin (G418), a potent aminoglycoside for the treatment of leishmaniasis at a 2.65-Å resolution, and Apramycin, shown to be a strong binder to the leishmanial ribosome lacking an antileishmanial activity at 1.4-Å resolution. The structural data, coupled with in vitro inhibition measurements on two strains of Leishmania , provide insight as to the source of the difference in inhibitory activity of different Aminoglycosides. The combined structural and physiological data sets the ground for rational design of new, and more specific, aminoglycoside derivatives as potential therapeutic agents against leishmaniasis.

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Section: In Vitro Inhibition Of Leishmania Donovani and Leishmania Majorsupporting

confidence: 75%

Identification of the molecular attributes required for aminoglycoside activity against Leishmania

Shalev

Kondo

Kopelyanskiy³

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

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“…In vitro growth inhibition studies of L. major and L. donovani showed that PAR and G418 were more potent than NEO, GEN, and APR. [120][121][122][123] PAR even exhibited antileishmanial activity against antimony-resistant strains. 124 This earned it a spot as a major ingredient of Leishcutan, a topical ointment used for the treatment of cutaneous leishmaniasis.…”

Section: Structure Mic (Mg ML à1mentioning

confidence: 99%

New trends in the use of aminoglycosides

Fosso

2014

Med. Chem. Commun.

100

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Despite their inherent toxicity and the acquired bacterial resistance that continuously threaten their long-term clinical use, aminoglycosides (AGs) still remain valuable components of the antibiotic armamentarium. Recent literature shows that the AGs’ role has been further expanded as multi-tasking players in different areas of study. This review aims at presenting some of the new trends observed in the use of AGs in the past decade, along with the current understanding of their mechanisms of action in various bacterial and eukaryotic cellular processes.

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Chemical system biology approach to identify multi-targeting FDA inhibitors for treating COVID-19 and associated health complications

Naik

Mattaparthi

Gupta

et al. 2021

Journal of Biomolecular Structure and Dynamics

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In view of many European countries and the USA leading to the second wave of COVID-19 pandemic, winter season, the evolution of new mutations in the spike protein, and no registered drugs and vaccines for COVID-19 treatment, the discovery of effective and novel therapeutic agents is urgently required. The degrees and frequencies of COVID-19 clinical complications are related to uncontrolled immune responses, secondary bacterial infections, diabetes, cardiovascular disease, hypertension, and chronic pulmonary diseases. It is essential to recognize that the drug repurposing strategy so far remains the only means to manage the disease burden of COVID-19. Despite some success of using single-target drugs in treating the disease, it is beyond suspicion that the virus will acquire drug resistance by acquiring mutations in the drug target. The possible synergistic inhibition of drug efficacy due to drug-drug interaction cannot be avoided while treating COVID-19 and allied clinical complications. Hence, to avoid the unintended development drug resistance and loss of efficacy due to drug-drug interaction, multi-target drugs can be promising tools for the most challenging disease. In the present work, we have carried out molecular docking studies of compounds from the FDA approved drug library, and the FDA approved and passed phase −1 drug libraries with ten therapeutic targets of COVID-19. Results showed that known drugs, including nine anti-inflammatory compounds, four antibiotics, six antidiabetic compounds, and one cardioprotective compound, could effectively inhibit multiple therapeutic targets of COVID-19. Further in-vitro , in vivo , and clinical studies will guide these drugs' proper allocation to treat COVID-19. Communicated by Ramaswamy H. Sarma

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Characterization of a compensatory mutant of Leishmania major that lacks ether lipids but exhibits normal growth, and G418 and hygromycin resistance

Cited by 3 publications

References 31 publications

Identification of the molecular attributes required for aminoglycoside activity against Leishmania

Identification of the molecular attributes required for aminoglycoside activity against Leishmania

New trends in the use of aminoglycosides

Chemical system biology approach to identify multi-targeting FDA inhibitors for treating COVID-19 and associated health complications

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