Comparative proteomic analysis of antimony-resistant and -susceptible Leishmania braziliensis and Leishmania infantum chagasi lines

Matrangolo, Fabiana S.V.; Liarte, Daniel Barbosa; Andrade, Laila C.; Melo, Melina F. de; Andrade, Juvana Moreira; Ferreira, Rafael; Santiago, André S.; Pirovani, Carlos Priminho; Silva-Pereira, Rosiane Aparecida da; Murta, Silvane Maria Fonseca

doi:10.1016/j.molbiopara.2013.06.006

Cited by 82 publications

(120 citation statements)

References 52 publications

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“…Several genes have been described to be involved in virulence and resistance to therapy (22,(25)(26)(27). Therefore, some of those genes related to treatment resistance and parasite virulence were also assessed.…”

Section: Discussionmentioning

confidence: 99%

“…Therefore, some of those genes related to treatment resistance and parasite virulence were also assessed. On the one hand, alpha-tubulin, which had been demonstrated to be more abundant in Sb(III)-resistant Leishmania strains (27), was analyzed. Interestingly, its gene expression was significantly reduced after treatment.…”

Section: Discussionmentioning

confidence: 99%

“…Recently, alpha-tubulin has been related to drug resistance (25,26). In fact, proteomic analyses demonstrated that this protein is commonly more abundant in Sb(III)-resistant Leishmania lines (27). The two compounds in our study significantly reduced alpha-tubulin gene expression (100% in control versus 71.16% Ϯ 12.88% in parasites exposed to 2b and 30.23% Ϯ 10.94% in those treated with 4b) (P Ͻ 0.01) (Fig.…”

Section: New Leishmanicidal Drugsmentioning

confidence: 99%

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Leishmanicidal Activities of Novel Methylseleno-Imidocarbamates

Fernández-Rubio

Campbell

Vacas

et al. 2015

Antimicrob Agents Chemother

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fThe generation of new antileishmanial drugs has become a priority. Selenium and its derivatives stand out as having promising leishmanicidal activity. In fact, some parasites express selenoproteins and metabolize selenium. Recently, selenium derivatives have shown the potential to reduce parasitemia, clinical manifestations, and mortality in parasite-infected mice. In this paper, after selecting four candidates according to drug similarity parameters, we observed that two of them, called compounds 2b [methyl-N,N=-di(thien-2-ylcarbonyl)-imidoselenocarbamate] and 4b [methyl-N,N=-di(5-nitrothien-3-ylcarbonyl)-imidoselenocarbamate], exhibit low 50% inhibitory concentrations (IC 50 s) (<3 M) and good selectivity indexes (SIs) (>5) in Leishmania major promastigotes and lack toxicity on macrophages. In addition, in analysis of their therapeutic potential against L. major in vitro infection, both compounds display a dramatic reduction of amastigote burden (ϳ80%) with sublethal concentrations. Furthermore, in macrophages, these selenocompounds induce nitric oxide production, which has been described to be critical for defense against intracellular pathogens. Compounds 2b and 4b were demonstrated to cause cell cycle arrest in G 1 . Interestingly, evaluation of expression of genes related to proliferation (PCNA), treatment resistance (ABC transporter and alpha-tubulin), and virulence (quinonoid dihydropteridine reductase [QDPR]) showed several alterations in gene expression profiling. All these results prompt us to propose both compounds as candidates to treat leishmanial infections.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: New Leishmanicidal Drugsmentioning

confidence: 99%

See 1 more Smart Citation

Leishmanicidal Activities of Novel Methylseleno-Imidocarbamates

Fernández-Rubio

Campbell

Vacas

et al. 2015

Antimicrob Agents Chemother

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“…(135)(136)(137)(138), Miscanthus sinensis (139), and Agrobacterium tumefaciens (117). The proteomics analysis in Leishmania spp.…”

Section: Metabolic Pathways Associated With Antimonite Resistancementioning

confidence: 99%

“…The proteomics analysis in Leishmania spp. showed that its mechanism of antimony resistance is complex, incorporating aspects of protein folding/chaperones, stress response, antioxidant/detoxification, diverse metabolic processes, RNA/DNA processing, and de novo protein biosynthesis (135)(136)(137)(138). The proteomic study of A. tumefaciens GW4 revealed that Sb(III) could influence the Ars resistance, the Sb(III) oxidase AnoA, phosphate metabolism, carbohydrate transport and metabolism, and the metabolism of lipids, purines, and amino acids ( Table 1).…”

Section: Metabolic Pathways Associated With Antimonite Resistancementioning

confidence: 99%

Microbial Antimony Biogeochemistry: Enzymes, Regulation, and Related Metabolic Pathways

Wang

Oremland

et al. 2016

Appl Environ Microbiol

160

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e Antimony (Sb) is a toxic metalloid that occurs widely at trace concentrations in soil, aquatic systems, and the atmosphere. Nowadays, with the development of its new industrial applications and the corresponding expansion of antimony mining activities, the phenomenon of antimony pollution has become an increasingly serious concern. In recent years, research interest in Sb has been growing and reflects a fundamental scientific concern regarding Sb in the environment. In this review, we summarize the recent research on bacterial antimony transformations, especially those regarding antimony uptake, efflux, antimonite oxidation, and antimonate reduction. We conclude that our current understanding of antimony biochemistry and biogeochemistry is roughly equivalent to where that of arsenic was some 20 years ago. This portends the possibility of future discoveries with regard to the ability of microorganisms to conserve energy for their growth from antimony redox reactions and the isolation of new species of "antimonotrophs."

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Heat Shock Proteins Revisited: Using a Mutasynthetically Generated Reblastatin Library to Compare the Inhibition of Human and Leishmania Hsp90s

Mohammadi-Ostad-Kalayeh

Stahl

Scheper

et al. 2018

ChemBioChem

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Thirteen new reblastatin derivatives, with alkynyl, amino and fluoro substituents on the aromatic ring, were prepared by a chemo-biosynthetic approach using an AHBA(-) mutant strain of Streptomyces hygroscopicus, the geldanamycin producer. The inhibitory potencies of these mutaproducts and of an extended library of natural products and derivatives were probed with purified heat shock proteins (Hsps), obtained from Leishmania braziliensis (LbHsp90) as well as from human sources (HsHsp90). We determined the activities of potential inhibitors by means of a displacement assay in which fluorescence-labelled ATP competes for the ATP binding sites of Hsps in the presence of the inhibitor in question. The results were compared with those of cell-based assays and, in selected cases, of isothermal titration calorimetry (ITC) measurements. In essence, reblastatin derivatives are also able to bind effectively to the ATP-binding site of LbHsp90, and for selected derivatives, moderate differences in binding to LbHsp90 and HsHsp90 were encountered. This work demonstrates that parasitic heat shock proteins can be developed as potential pharmaceutical targets.

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Comparative proteomic analysis of antimony-resistant and -susceptible Leishmania braziliensis and Leishmania infantum chagasi lines

Cited by 82 publications

References 52 publications

Leishmanicidal Activities of Novel Methylseleno-Imidocarbamates

Leishmanicidal Activities of Novel Methylseleno-Imidocarbamates

Microbial Antimony Biogeochemistry: Enzymes, Regulation, and Related Metabolic Pathways

Heat Shock Proteins Revisited: Using a Mutasynthetically Generated Reblastatin Library to Compare the Inhibition of Human and Leishmania Hsp90s

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