RESUMEN
The genus Striga, also called "witchweed", is a member of the family Orobanchaceae, which is a major family of root-parasitic plants. Striga can lead to the formation of seed stocks in the soil and to explosive expansion with enormous seed production and stability once the crops they parasitize are cultivated. Understanding the molecular mechanism underlying the communication between Striga and their host plants through natural seed germination stimulants, "strigolactones (SLs)", is required to develop the technology for Striga control. This review outlines recent findings on the SL perception mechanism, which have been accumulated in Striga hermonthica by the similarity of the protein components that regulate SL signaling in nonparasitic model plants, including Arabidopsis and rice. HTL/KAI2 homologs were identified as SL receptors in the process of Striga seed germination. Recently, this molecular basis has further promoted the development of various types of SL agonists/antagonists as seed germination stimulants or inhibitors. Such chemical compounds are also useful to elucidate the dynamic behavior of SL receptors and the regulation of SL signaling.
Asunto(s)
Productos Agrícolas/parasitología , Lactonas/metabolismo , Reguladores del Crecimiento de las Plantas/metabolismo , Striga/crecimiento & desarrollo , Control de Malezas , Germinación/efectos de los fármacos , Interacciones Huésped-Parásitos/efectos de los fármacos , Lactonas/agonistas , Lactonas/antagonistas & inhibidores , Reguladores del Crecimiento de las Plantas/agonistas , Reguladores del Crecimiento de las Plantas/antagonistas & inhibidores , Raíces de Plantas/parasitología , Semillas/efectos de los fármacos , Semillas/crecimiento & desarrollo , Semillas/fisiología , Transducción de Señal/efectos de los fármacos , Striga/efectos de los fármacos , Striga/fisiología , Control de Malezas/métodosRESUMEN
Malaria parasites repair DNA double-strand breaks (DSBs) primarily through homologous recombination (HR). Here, because the unrepaired DSBs lead to the death of the unicellular parasite Plasmodium falciparum, we investigated its recombinase, PfRad51, as a potential drug target. Undertaking an in silico screening approach, we identified a compound, B02, that docks to the predicted tertiary structure of PfRad51 with high affinity. B02 inhibited a drug-sensitive P. falciparum strain (3D7) and multidrug-resistant parasite (Dd2) in culture, with IC50 values of 8 and 3 µm, respectively. We found that B02 is more potent against these P. falciparum strains than against mammalian cell lines. Our findings also revealed that the antimalarial activity of B02 synergizes with those of two first-line malaria drugs, artemisinin (ART) and chloroquine (CQ), lowering the IC50 values of ART and CQ by 15- and 8-fold, respectively. Our results also provide mechanistic insights into the anti-parasitic activity of B02, indicating that it blocks the ATPase and strand-exchange activities of PfRad51 and abrogates the formation of PfRad51 foci on damaged DNA at chromosomal sites, probably by blocking homomeric interactions of PfRad51 proteins. The B02-mediated PfRad51 disruption led to the accumulation of unrepaired parasitic DNA and rendered parasites more sensitive to DNA-damaging agents, including ART. Our findings provide a rationale for targeting the Plasmodium DSB repair pathway in combination with ART. We propose that identification of a specific inhibitor of HR in Plasmodium may enable investigations of HR's role in Plasmodium biology, including generation of antigenic diversity.
Asunto(s)
Antimaláricos , Artemisininas , Cloroquina , Resistencia a Múltiples Medicamentos/efectos de los fármacos , Inhibidores Enzimáticos , Lactonas , Plasmodium falciparum/enzimología , Proteínas Protozoarias/antagonistas & inhibidores , Recombinasa Rad51/antagonistas & inhibidores , Antimaláricos/química , Antimaláricos/farmacología , Artemisininas/agonistas , Artemisininas/química , Artemisininas/farmacología , Cloroquina/agonistas , Cloroquina/química , Cloroquina/farmacología , Simulación por Computador , Sinergismo Farmacológico , Inhibidores Enzimáticos/química , Inhibidores Enzimáticos/farmacología , Humanos , Lactonas/agonistas , Lactonas/química , Lactonas/farmacología , Simulación del Acoplamiento Molecular , Plasmodium falciparum/genética , Proteínas Protozoarias/química , Proteínas Protozoarias/genética , Proteínas Protozoarias/metabolismo , Recombinasa Rad51/química , Recombinasa Rad51/genética , Recombinasa Rad51/metabolismoRESUMEN
Strigolactones (SLs) are small carotenoid-derived molecules that possess a wide spectrum of functions, including plant hormonal activities and chemical mediation of rhizosphere communication with both root parasitic plants and symbiotic arbuscular mycorrhizal fungi. Chemicals that regulate the functions of SLs may therefore have the potential to become widely used in agricultural applications. For example, various SL analogs and mimics have been developed to reduce the seed banks of root parasites in the field. Other analogs and mimics act selectively to suppress branching, with weak, or no stimulation, of germination in root parasites. In addition, some antagonists for SL receptors have been developed based on the mechanisms of SL perception. A better understanding of the modes of action of SL perception by various receptors will help to support the design of SL analogs, mimics, and antagonists with high activity and selectivity. Here, we review the compounds reported so far from the viewpoint of their selectivity to their targets, and the possibilities for their use in agriculture.
Asunto(s)
Productos Agrícolas/efectos de los fármacos , Lactonas/farmacología , Desarrollo de la Planta/efectos de los fármacos , Reguladores del Crecimiento de las Plantas/farmacología , Agricultura/métodos , Productos Agrícolas/crecimiento & desarrollo , Lactonas/agonistas , Lactonas/antagonistas & inhibidores , Reguladores del Crecimiento de las Plantas/agonistas , Reguladores del Crecimiento de las Plantas/antagonistas & inhibidoresRESUMEN
The autoinducer (AI) that initiates the quorum sensing (QS) signaling cascade in Pseudomonas aeruginosa is an acyl-homoserine lactone (acyl-HSL). We initiated a study of the requirements for binding of the AI to its protein effector LasR by synthesizing a library of analogs with the HSL moiety replaced with different amines and alcohols. We tested each compound for both agonist and antagonist activity using a QS-controlled reporter gene assay and found several new agonists and antagonists. A representative antagonist was further tested for its ability to inhibit virulence factors. This data progresses our understanding of the LasR-AI interaction toward the rational design of therapeutic inhibitors of QS.