The stepwise selection for ketoconazole resistance induces upregulation of C14-demethylase (CYP51) in Leishmania amazonensis

Andrade-Neto, Valter Viana; Matos-Guedes, Herbert Leonel de; Gomes, Daniel; Canto‐Cavalheiro, Marilene M.; Rossi-Bergmann, Bartira; Torres-Santos, Eduardo Caio

doi:10.1590/s0074-02762012000300018

Cited by 11 publications

(10 citation statements)

References 17 publications

(19 reference statements)

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“…Recent studies have also shown that the resistance level of Leishmania amazonensis to ketoconazole was directly proportional to the level of expression of CYP51 Table 3 Expression difference of high-death-correlated genes between embryo and liver in 1.00 mg/L group. mRNA (Andrade-Neto et al, 2012), which is consistent with our results. Table 3 lists the difference in expression of high-deathcorrelated (HDC) genes of adult zebrafish (the ten highest negatively correlated genes) between the embryos and the livers of adult zebrafish in the group exposed to 1.00 mg/L difenoconazole.…”

Section: Discussionsupporting

confidence: 94%

Occurrence and origin of sensitivity toward difenoconazole in zebrafish (Danio reio) during different life stages

et al. 2015

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Section: Discussionsupporting

confidence: 94%

Occurrence and origin of sensitivity toward difenoconazole in zebrafish (Danio reio) during different life stages

et al. 2015

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“…Ramanathan et al (2011) [83] demonstrated efficacy in the treatment of CL by Leishmania panamensis . With respect to ketoconazole resistance, Andrade-Neto et al (2012) [84] demonstrated that Leishmania amazonensis can up-regulate the C-14 demethylase in response to ketoconazole, which may contribute to its resistance to this drug.…”

Section: Discussionmentioning

confidence: 99%

Pentavalent Antimonials Combined with Other Therapeutic Alternatives for the Treatment of Cutaneous and Mucocutaneous Leishmaniasis: A Systematic Review

Berbert

Mello

Nassif

et al. 2018

Dermatology Research and Practice

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The first choice drugs for the treatment of cutaneous and mucocutaneous leishmaniasis are pentavalent antimonials, sodium stibogluconate, or meglumine antimoniate. However, the treatment with these drugs is expensive, can cause serious adverse effects, and is not always effective. The combination of two drugs by different routes or the combination of an alternative therapy with systemic therapy can increase the efficacy and decrease the collateral effects caused by the reference drugs. In this systematic review we investigated publications that described a combination of nonconventional treatment for cutaneous and mucocutaneous with pentavalent antimonials. A literature review was performed in the databases Web of Knowledge and PubMed in the period from 01st of December 2004 to 01st of June 2017, according to Prisma statement. Only clinical trials involving the treatment for cutaneous or mucocutaneous leishmaniasis, in English, and with available abstract were added. Other types of publications, such as reviews, case reports, comments to the editor, letters, interviews, guidelines, and errata, were excluded. Sixteen articles were selected and the pentavalent antimonials were administered in combination with pentoxifylline, granulocyte macrophage colony-stimulating factor, imiquimod, intralesional sodium stibogluconate, ketoconazole, silver-containing polyester dressing, lyophilized LEISH-F1 protein, cryotherapy, topical honey, and omeprazole. In general, the combined therapy resulted in high rates of clinical cure and when relapse or recurrence was reported, it was higher in the groups treated with pentavalent antimonials alone. The majority of the articles included in this review showed that cure rate ranged from 70 to 100% in patients treated with the combinations. Serious adverse effects were not observed in patients treated with drugs combination. The combination of other drugs or treatment modalities with pentavalent antimonials has proved to be effective for cutaneous and mucocutaneous leishmaniasis and for most seemed to be safe. However, new randomized, controlled, and multicentric clinical trials with more robust samples should be performed, especially the combination with immunomodulators.

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“…But a number of studies have already reported on the inhibition of the T . brucei and Leishmania enzymes with CYP51 inhibitors [ 81 – 83 ]. However, these data were not present in the TDR Targets and/or ChEMBL releases used to build the network.…”

Section: Resultsmentioning

confidence: 99%

A Multilayer Network Approach for Guiding Drug Repositioning in Neglected Diseases

et al. 2016

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Drug development for neglected diseases has been historically hampered due to lack of market incentives. The advent of public domain resources containing chemical information from high throughput screenings is changing the landscape of drug discovery for these diseases. In this work we took advantage of data from extensively studied organisms like human, mouse, E. coli and yeast, among others, to develop a novel integrative network model to prioritize and identify candidate drug targets in neglected pathogen proteomes, and bioactive drug-like molecules. We modeled genomic (proteins) and chemical (bioactive compounds) data as a multilayer weighted network graph that takes advantage of bioactivity data across 221 species, chemical similarities between 1.7 105 compounds and several functional relations among 1.67 105 proteins. These relations comprised orthology, sharing of protein domains, and shared participation in defined biochemical pathways. We showcase the application of this network graph to the problem of prioritization of new candidate targets, based on the information available in the graph for known compound-target associations. We validated this strategy by performing a cross validation procedure for known mouse and Trypanosoma cruzi targets and showed that our approach outperforms classic alignment-based approaches. Moreover, our model provides additional flexibility as two different network definitions could be considered, finding in both cases qualitatively different but sensible candidate targets. We also showcase the application of the network to suggest targets for orphan compounds that are active against Plasmodium falciparum in high-throughput screens. In this case our approach provided a reduced prioritization list of target proteins for the query molecules and showed the ability to propose new testable hypotheses for each compound. Moreover, we found that some predictions highlighted by our network model were supported by independent experimental validations as found post-facto in the literature.

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The stepwise selection for ketoconazole resistance induces upregulation of C14-demethylase (CYP51) in Leishmania amazonensis

Cited by 11 publications

References 17 publications

Occurrence and origin of sensitivity toward difenoconazole in zebrafish (Danio reio) during different life stages

Occurrence and origin of sensitivity toward difenoconazole in zebrafish (Danio reio) during different life stages

Pentavalent Antimonials Combined with Other Therapeutic Alternatives for the Treatment of Cutaneous and Mucocutaneous Leishmaniasis: A Systematic Review

A Multilayer Network Approach for Guiding Drug Repositioning in Neglected Diseases

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