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1.
Commun Biol ; 5(1): 128, 2022 02 11.
Artículo en Inglés | MEDLINE | ID: mdl-35149760

RESUMEN

In vitro evolution and whole genome analysis were used to comprehensively identify the genetic determinants of chemical resistance in Saccharomyces cerevisiae. Sequence analysis identified many genes contributing to the resistance phenotype as well as numerous amino acids in potential targets that may play a role in compound binding. Our work shows that compound-target pairs can be conserved across multiple species. The set of 25 most frequently mutated genes was enriched for transcription factors, and for almost 25 percent of the compounds, resistance was mediated by one of 100 independently derived, gain-of-function SNVs found in a 170 amino acid domain in the two Zn2C6 transcription factors YRR1 and YRM1 (p < 1 × 10-100). This remarkable enrichment for transcription factors as drug resistance genes highlights their important role in the evolution of antifungal xenobiotic resistance and underscores the challenge to develop antifungal treatments that maintain potency.


Asunto(s)
Proteínas de Saccharomyces cerevisiae , Saccharomyces cerevisiae , Regulación Fúngica de la Expresión Génica , Saccharomyces cerevisiae/genética , Saccharomyces cerevisiae/metabolismo , Proteínas de Saccharomyces cerevisiae/genética , Proteínas de Saccharomyces cerevisiae/metabolismo , Factores de Transcripción/metabolismo , Xenobióticos/metabolismo , Xenobióticos/farmacología
2.
Nat Plants ; 6(5): 483-491, 2020 05.
Artículo en Inglés | MEDLINE | ID: mdl-32415295

RESUMEN

Reduced insect pest populations found on long-term organic farms have mostly been attributed to increased biodiversity and abundance of beneficial predators, as well as to changes in plant nutrient content. However, the role of plant resistance has largely been ignored. Here, we determine whether host plant resistance mediates decreased pest populations in organic systems and identify potential underpinning mechanisms. We demonstrate that fewer numbers of leafhoppers (Circulifer tenellus) settle on tomatoes (Solanum lycopersicum) grown using organic management as compared to conventional. We present multiple lines of evidence, including rhizosphere soil microbiome sequencing, chemical analysis and transgenic approaches, to demonstrate that changes in leafhopper settling between organically and conventionally grown tomatoes are dependent on salicylic acid accumulation in plants and mediated by rhizosphere microbial communities. These results suggest that organically managed soils and microbial communities may play an unappreciated role in reducing plant attractiveness to pests by increasing plant resistance.


Asunto(s)
Agricultura Orgánica , Control Biológico de Vectores , Defensa de la Planta contra la Herbivoria , Animales , Hemípteros , Solanum lycopersicum/fisiología , Agricultura Orgánica/métodos , Rizosfera , Microbiología del Suelo
3.
Nat Commun ; 11(1): 1780, 2020 04 14.
Artículo en Inglés | MEDLINE | ID: mdl-32286267

RESUMEN

A promising new compound class for treating human malaria is the imidazolopiperazines (IZP) class. IZP compounds KAF156 (Ganaplacide) and GNF179 are effective against Plasmodium symptomatic asexual blood-stage infections, and are able to prevent transmission and block infection in animal models. But despite the identification of resistance mechanisms in P. falciparum, the mode of action of IZPs remains unknown. To investigate, we here combine in vitro evolution and genome analysis in Saccharomyces cerevisiae with molecular, metabolomic, and chemogenomic methods in P. falciparum. Our findings reveal that IZP-resistant S. cerevisiae clones carry mutations in genes involved in Endoplasmic Reticulum (ER)-based lipid homeostasis and autophagy. In Plasmodium, IZPs inhibit protein trafficking, block the establishment of new permeation pathways, and cause ER expansion. Our data highlight a mechanism for blocking parasite development that is distinct from those of standard compounds used to treat malaria, and demonstrate the potential of IZPs for studying ER-dependent protein processing.


Asunto(s)
Antimaláricos/farmacología , Plasmodium falciparum/efectos de los fármacos , Cromatografía Líquida de Alta Presión , Retículo Endoplásmico/efectos de los fármacos , Retículo Endoplásmico/metabolismo , Concentración 50 Inhibidora , Espectrometría de Masas , Proteínas Protozoarias/metabolismo , Pirazoles/farmacología , Saccharomyces cerevisiae/efectos de los fármacos , Saccharomyces cerevisiae/metabolismo , Vías Secretoras/efectos de los fármacos
4.
Science ; 362(6419)2018 12 07.
Artículo en Inglés | MEDLINE | ID: mdl-30523084

RESUMEN

To discover leads for next-generation chemoprotective antimalarial drugs, we tested more than 500,000 compounds for their ability to inhibit liver-stage development of luciferase-expressing Plasmodium spp. parasites (681 compounds showed a half-maximal inhibitory concentration of less than 1 micromolar). Cluster analysis identified potent and previously unreported scaffold families as well as other series previously associated with chemoprophylaxis. Further testing through multiple phenotypic assays that predict stage-specific and multispecies antimalarial activity distinguished compound classes that are likely to provide symptomatic relief by reducing asexual blood-stage parasitemia from those which are likely to only prevent malaria. Target identification by using functional assays, in vitro evolution, or metabolic profiling revealed 58 mitochondrial inhibitors but also many chemotypes possibly with previously unidentified mechanisms of action.


Asunto(s)
Antimaláricos/farmacología , Quimioprevención , Descubrimiento de Drogas , Malaria/prevención & control , Plasmodium/efectos de los fármacos , Antimaláricos/química , Antimaláricos/aislamiento & purificación , Antimaláricos/uso terapéutico , Evaluación Preclínica de Medicamentos , Humanos , Mitocondrias/efectos de los fármacos , Plasmodium/crecimiento & desarrollo
5.
J Cheminform ; 10(1): 6, 2018 Feb 20.
Artículo en Inglés | MEDLINE | ID: mdl-29464421

RESUMEN

Given that many antifungal medications are susceptible to evolved resistance, there is a need for novel drugs with unique mechanisms of action. Inhibiting the essential proton pump Pma1p, a P-type ATPase, is a potentially effective therapeutic approach that is orthogonal to existing treatments. We identify NSC11668 and hitachimycin as structurally distinct antifungals that inhibit yeast ScPma1p. These compounds provide new opportunities for drug discovery aimed at this important target.

6.
Nat Commun ; 8: 14493, 2017 02 16.
Artículo en Inglés | MEDLINE | ID: mdl-28205516

RESUMEN

Vector-borne pathogens influence host characteristics relevant to host-vector contact, increasing pathogen transmission and survival. Previously, we demonstrated that infection with Turnip mosaic virus, a member of one of the largest families of plant-infecting viruses, increases vector attraction and reproduction on infected hosts. These changes were due to a single viral protein, NIa-Pro. Here we show that NIa-Pro responds to the presence of the aphid vector during infection by relocalizing to the vacuole. Remarkably, vacuolar localization is required for NIa-Pro's ability to enhance aphid reproduction on host plants, vacuole localization disappears when aphids are removed, and this phenomenon occurs for another potyvirus, Potato virus Y, suggesting a conserved role for the protein in vector-host interactions. Taken together, these results suggest that potyviruses dynamically respond to the presence of their vectors, promoting insect performance and transmission only when needed.


Asunto(s)
Endopeptidasas/metabolismo , Interacciones Huésped-Patógeno , Insectos Vectores/virología , Potyvirus/metabolismo , Proteínas Virales/metabolismo , Animales , Áfidos , Arabidopsis/genética , Arabidopsis/virología , Fertilidad , Enfermedades de las Plantas/virología , Hojas de la Planta/virología , Virus de Plantas/patogenicidad , Plantas Modificadas Genéticamente , Potyvirus/enzimología , Potyvirus/patogenicidad , Nicotiana/virología , Virosis/transmisión
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