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1.
Proc Natl Acad Sci U S A ; 120(2): e2210181120, 2023 01 10.
Artículo en Inglés | MEDLINE | ID: mdl-36595704

RESUMEN

Malaria, caused by Plasmodium parasites is a severe disease affecting millions of people around the world. Plasmodium undergoes obligatory development and replication in the hepatocytes, before initiating the life-threatening blood-stage of malaria. Although the natural immune responses impeding Plasmodium infection and development in the liver are key to controlling clinical malaria and transmission, those remain relatively unknown. Here we demonstrate that the DNA of Plasmodium parasites is sensed by cytosolic AIM2 (absent in melanoma 2) receptors in the infected hepatocytes, resulting in Caspase-1 activation. Remarkably, Caspase-1 was observed to undergo unconventional proteolytic processing in hepatocytes, resulting in the activation of the membrane pore-forming protein, Gasdermin D, but not inflammasome-associated proinflammatory cytokines. Nevertheless, this resulted in the elimination of Plasmodium-infected hepatocytes and the control of malaria infection in the liver. Our study uncovers a pathway of natural immunity critical for the control of malaria in the liver.


Asunto(s)
Malaria , Parásitos , Plasmodium , Animales , Humanos , Hepatocitos/metabolismo , Hígado , Malaria/parasitología , Caspasas/metabolismo , Proteínas de Unión al ADN/metabolismo
2.
Antimicrob Agents Chemother ; 68(5): e0028024, 2024 May 02.
Artículo en Inglés | MEDLINE | ID: mdl-38587391

RESUMEN

Testing Plasmodium vivax antimicrobial sensitivity is limited to ex vivo schizont maturation assays, which preclude determining the IC50s of delayed action antimalarials such as doxycycline. Using Plasmodium cynomolgi as a model for P. vivax, we determined the physiologically significant delayed death effect induced by doxycycline [IC50(96 h), 1,401 ± 607 nM]. As expected, IC50(96 h) to chloroquine (20.4 nM), piperaquine (12.6 µM), and tafenoquine (1,424 nM) were not affected by extended exposure.


Asunto(s)
Aminoquinolinas , Antimaláricos , Doxiciclina , Piperazinas , Plasmodium cynomolgi , Plasmodium vivax , Doxiciclina/farmacología , Antimaláricos/farmacología , Aminoquinolinas/farmacología , Plasmodium vivax/efectos de los fármacos , Plasmodium cynomolgi/efectos de los fármacos , Cloroquina/farmacología , Animales , Malaria Vivax/tratamiento farmacológico , Malaria Vivax/parasitología , Quinolinas/farmacología , Concentración 50 Inhibidora , Humanos , Pruebas de Sensibilidad Parasitaria
3.
J Nat Prod ; 87(2): 315-321, 2024 02 23.
Artículo en Inglés | MEDLINE | ID: mdl-38262446

RESUMEN

Trichothecenes (TCNs) are a large group of tricyclic sesquiterpenoid mycotoxins that have intriguing structural features and remarkable biological activities. Herein, we focused on three TCNs (anguidine, verrucarin A, and verrucarol) and their ability to target both the blood and liver stages of Plasmodium species, the parasite responsible for malaria. Anguidine and verrucarin A were found to be highly effective against the blood and liver stages of malaria, while verrucarol had no effect at the highest concentration tested. However, these compounds were also found to be cytotoxic and, thus, not selective, making them unsuitable for drug development. Nonetheless, they could be useful as chemical probes for protein synthesis inhibitors due to their direct impact on parasite synthesis processes.


Asunto(s)
Antimaláricos , Malaria , Plasmodium , Tricotecenos , Humanos , Antimaláricos/farmacología , Antimaláricos/química , Tricotecenos/farmacología , Malaria/tratamiento farmacológico , Malaria/parasitología , Hígado , Plasmodium falciparum
4.
J Infect Dis ; 227(10): 1121-1126, 2023 05 12.
Artículo en Inglés | MEDLINE | ID: mdl-36478252

RESUMEN

The lack of a long-term in vitro culture method has severely restricted the study of Plasmodium vivax, in part because it limits genetic manipulation and reverse genetics. We used the recently optimized Plasmodium cynomolgi Berok in vitro culture model to investigate the putative P. vivax drug resistance marker MDR1 Y976F. Introduction of this mutation using clustered regularly interspaced short palindromic repeats-CRISPR-associated protein 9 (CRISPR-Cas9) increased sensitivity to mefloquine, but had no significant effect on sensitivity to chloroquine, amodiaquine, piperaquine, and artesunate. To our knowledge, this is the first reported use of CRISPR-Cas9 in P. cynomolgi, and the first reported integrative genetic manipulation of this species.


Asunto(s)
Antimaláricos , Plasmodium cynomolgi , Mefloquina/farmacología , Antimaláricos/farmacología , Cloroquina/farmacología , Plasmodium vivax/genética , Resistencia a Medicamentos/genética , Resistencia a Múltiples Medicamentos/genética , Plasmodium falciparum
5.
Malar J ; 21(1): 264, 2022 Sep 13.
Artículo en Inglés | MEDLINE | ID: mdl-36100902

RESUMEN

BACKGROUND: Sporozoites isolated from the salivary glands of Plasmodium-infected mosquitoes are a prerequisite for several basic and pre-clinical applications. Although salivary glands are pooled to maximize sporozoite recovery, insufficient yields pose logistical and analytical hurdles; thus, predicting yields prior to isolation would be valuable. Preceding oocyst densities in the midgut is an obvious candidate. However, it is unclear whether current understanding of its relationship with sporozoite densities can be used to maximize yields, or whether it can capture the potential density-dependence in rates of sporozoite invasion of the salivary glands. METHODS: This study presents a retrospective analysis of Anopheles stephensi mosquitoes infected with two strains of the rodent-specific Plasmodium berghei. Mean oocyst densities were estimated in the midguts earlier in the infection (11-15 days post-blood meal), with sporozoites pooled from the salivary glands later in the infection (17-29 days). Generalized linear mixed effects models were used to determine if (1) mean oocyst densities can predict sporozoite yields from pooled salivary glands, (2) whether these densities can capture differences in rates of sporozoite invasion of salivary glands, and (3), if the interaction between oocyst densities and time could be leveraged to boost overall yields. RESULTS: The non-linear effect of mean oocyst densities confirmed the role of density-dependent constraints in limiting yields beyond certain oocyst densities. Irrespective of oocyst densities however, the continued invasion of salivary glands by the sporozoites boosted recoveries over time (17-29 days post-blood meal) for either parasite strain. CONCLUSIONS: Sporozoite invasion of the salivary glands over time can be leveraged to maximize yields for P. berghei. In general, however, invasion of the salivary glands over time is a critical fitness determinant for all Plasmodium species (extrinsic incubation period, EIP). Thus, delaying sporozoite collection could, in principle, substantially reduce dissection effort for any parasite within the genus, with the results also alluding to the potential for changes in sporozoites densities over time to modify infectivity for the next host.


Asunto(s)
Anopheles , Esporozoítos , Animales , Anopheles/parasitología , Plasmodium berghei , Estudios Retrospectivos , Glándulas Salivales/parasitología
6.
Bioorg Med Chem ; 57: 116629, 2022 03 01.
Artículo en Inglés | MEDLINE | ID: mdl-35091169

RESUMEN

Malaria is a prevalent and lethal disease. The fast emergence and spread of resistance to current therapies is a major concern and the development of a novel line of therapy that could overcome, the problem of drug resistance, is imperative. Screening of a set of compounds with drug/natural product-based sub-structural motifs led to the identification of spirocyclic chroman-4-one 1 with promising antimalarial activity against the chloroquine-resistant Dd2 and chloroquine-sensitive 3D7 strains of the parasite. Extensive structure-activity and structure-property relationship studies were conducted to identify the essential features necessary for its activity and properties.


Asunto(s)
Antimaláricos/farmacología , Cromanos/farmacología , Malaria/tratamiento farmacológico , Plasmodium/efectos de los fármacos , Compuestos de Espiro/farmacología , Antimaláricos/síntesis química , Antimaláricos/química , Supervivencia Celular/efectos de los fármacos , Cromanos/síntesis química , Cromanos/química , Cristalografía por Rayos X , Relación Dosis-Respuesta a Droga , Células Hep G2 , Humanos , Modelos Moleculares , Estructura Molecular , Pruebas de Sensibilidad Parasitaria , Compuestos de Espiro/síntesis química , Compuestos de Espiro/química , Relación Estructura-Actividad
7.
Mar Drugs ; 20(9)2022 Sep 14.
Artículo en Inglés | MEDLINE | ID: mdl-36135765

RESUMEN

Chemical investigation of an Antarctic deep-water octocoral has led to the isolation of four new compounds, including three illudalane sesquiterpenoids (1-3) related to the alcyopterosins, a highly oxidized steroid, alcyosterone (5), and five known alcyopterosins (4, 6-9). The structures were established by extensive 1D and 2D NMR analyses, while 9 was verified by XRD. Alcyopterosins are unusual for their nitrate ester functionalization and have been characterized with cytotoxicity related to their DNA binding properties. Alcyopterosins V (3) and E (4) demonstrated single-digit micromolar activity against Clostridium difficile, an intestinal bacterium capable of causing severe diarrhea that is increasingly associated with drug resistance. Alcyosterone (5) and several alcyopterosins were similarly potent against the protist Leishmania donovani, the causative agent of leishmaniasis, a disfiguring disease that can be fatal if not treated. While the alcyopterosin family of sesquiterpenes is known for mild cytotoxicity, the observed activity against C. difficile and L. donovani is selective for the infectious agents.


Asunto(s)
Antozoos , Clostridioides difficile , Leishmania donovani , Sesquiterpenos , Animales , Regiones Antárticas , Antozoos/química , ADN , Ésteres , Nitratos , Sesquiterpenos/química , Agua
8.
Antimicrob Agents Chemother ; 65(7): e0001721, 2021 06 17.
Artículo en Inglés | MEDLINE | ID: mdl-33846135

RESUMEN

Naegleria fowleri is a pathogenic free-living amoeba that is commonly found in warm freshwater and can cause a rapidly fulminant disease known as primary amoebic meningoencephalitis (PAM). New drugs are urgently needed to treat PAM, as the fatality rate is >97%. Until recently, few advances have been made in the discovery of new drugs for N. fowleri, and one drawback is the lack of validated tools and methods to enhance drug discovery and diagnostics research. In this study, we aimed to validate alternative methods to assess cell proliferation that are commonly used for other cell types and develop a novel drug screening assay to evaluate drug efficacy on N. fowleri replication. EdU (5-ethynyl-2'-deoxyuridine) is a pyrimidine analog of thymidine that can be used as a quantitative endpoint for cell proliferation. EdU incorporation is detected via a copper catalyzed click reaction with an Alexa Fluor-linked azide. EdU incorporation in replicating N. fowleri was validated using fluorescence microscopy, and quantitative methods for assessing EdU incorporation were developed by using an imaging flow cytometer. Currently used PAM therapeutics inhibited N. fowleri replication and EdU incorporation in vitro. EdA (7-deaza-2'-deoxy-7-ethynyladenosine), an adenine analog, also was incorporated by N. fowleri but was more cytotoxic than EdU. In summary, EdU incorporation could be used as a complimentary method for drug discovery for these neglected pathogens.


Asunto(s)
Infecciones Protozoarias del Sistema Nervioso Central , Naegleria fowleri , Preparaciones Farmacéuticas , Proliferación Celular , Descubrimiento de Drogas , Humanos
9.
Nature ; 522(7556): 315-20, 2015 06 18.
Artículo en Inglés | MEDLINE | ID: mdl-26085270

RESUMEN

There is an urgent need for new drugs to treat malaria, with broad therapeutic potential and novel modes of action, to widen the scope of treatment and to overcome emerging drug resistance. Here we describe the discovery of DDD107498, a compound with a potent and novel spectrum of antimalarial activity against multiple life-cycle stages of the Plasmodium parasite, with good pharmacokinetic properties and an acceptable safety profile. DDD107498 demonstrates potential to address a variety of clinical needs, including single-dose treatment, transmission blocking and chemoprotection. DDD107498 was developed from a screening programme against blood-stage malaria parasites; its molecular target has been identified as translation elongation factor 2 (eEF2), which is responsible for the GTP-dependent translocation of the ribosome along messenger RNA, and is essential for protein synthesis. This discovery of eEF2 as a viable antimalarial drug target opens up new possibilities for drug discovery.


Asunto(s)
Antimaláricos/farmacología , Regulación de la Expresión Génica/efectos de los fármacos , Malaria/parasitología , Plasmodium/efectos de los fármacos , Plasmodium/metabolismo , Biosíntesis de Proteínas/efectos de los fármacos , Quinolinas/farmacología , Animales , Antimaláricos/administración & dosificación , Antimaláricos/efectos adversos , Antimaláricos/farmacocinética , Descubrimiento de Drogas , Femenino , Estadios del Ciclo de Vida/efectos de los fármacos , Hígado/efectos de los fármacos , Hígado/parasitología , Malaria/tratamiento farmacológico , Masculino , Modelos Moleculares , Factor 2 de Elongación Peptídica/antagonistas & inhibidores , Factor 2 de Elongación Peptídica/metabolismo , Plasmodium/genética , Plasmodium/crecimiento & desarrollo , Plasmodium berghei/efectos de los fármacos , Plasmodium berghei/fisiología , Plasmodium falciparum/efectos de los fármacos , Plasmodium falciparum/metabolismo , Plasmodium vivax/efectos de los fármacos , Plasmodium vivax/metabolismo , Quinolinas/administración & dosificación , Quinolinas/química , Quinolinas/farmacocinética
10.
Artículo en Inglés | MEDLINE | ID: mdl-32071043

RESUMEN

Balamuthia mandrillaris is an under-reported, pathogenic free-living amoeba that causes Balamuthia amoebic encephalitis (BAE) and cutaneous skin infections. Although cutaneous infections are not typically lethal, BAE with or without cutaneous involvement is usually fatal. This is due to the lack of drugs that are both efficacious and can cross the blood-brain barrier. We aimed to discover new leads for drug discovery by screening the open-source Medicines for Malaria Venture (MMV) Malaria Box and MMV Pathogen Box, with 800 compounds total. From an initial single point screen at 1 and 10 µM, we identified 54 hits that significantly inhibited the growth of B. mandrillarisin vitro Hits were reconfirmed in quantitative dose-response assays and 23 compounds (42.6%) were confirmed with activity greater than miltefosine, the current standard of care.


Asunto(s)
Amebicidas/farmacología , Antimaláricos/farmacología , Balamuthia mandrillaris/efectos de los fármacos , Amebiasis/parasitología , Animales , Balamuthia mandrillaris/crecimiento & desarrollo , Simulación por Computador , Relación Dosis-Respuesta a Droga , Descubrimiento de Drogas , Evaluación Preclínica de Medicamentos , Femenino , Papio , Embarazo
11.
J Nat Prod ; 83(5): 1553-1562, 2020 05 22.
Artículo en Inglés | MEDLINE | ID: mdl-32281798

RESUMEN

From the CH2Cl2 extract of the Antarctic sponge Dendrilla antarctica we found spongian diterpenes, including previously reported aplysulphurin (1), tetrahydroaplysulphurin-1 (2), membranolide (3), and darwinolide (4), utilizing a CH2Cl2/MeOH extraction scheme. However, the extracts also yielded diterpenes bearing one or more methyl acetal functionalities (5-9), two of which are previously unreported, while others are revised here. Further investigation of diterpene reactivity led to additional new metabolites (10-12), which identified them as well as the methyl acetals as artifacts from methanolysis of aplysulphurin. The bioactivity of the methanolysis products, membranoids A-H (5-12), as well as natural products 1-4, were assessed for activity against Leishmania donovani-infected J774A.1 macrophages, revealing insights into their structure/activity relationships. Four diterpenes, tetrahydroaplysulphurin-1 (2) as well as membranoids B (6), D (8), and G (11), displayed low micromolar activity against L. donovani with no discernible cytotoxicity against uninfected J774A.1 cells. Leishmaniasis is a neglected tropical disease that affects one million people every year and can be fatal if left untreated.


Asunto(s)
Productos Biológicos/farmacología , Diterpenos/farmacología , Leishmania donovani/efectos de los fármacos , Parásitos/efectos de los fármacos , Animales , Regiones Antárticas , Diterpenos/química , Humanos , Estructura Molecular
12.
Mar Drugs ; 18(6)2020 Jun 23.
Artículo en Inglés | MEDLINE | ID: mdl-32586020

RESUMEN

The Antarctic sponge Dendrilla antarctica is rich in defensive terpenoids with promising antimicrobial potential. Investigation of this demosponge has resulted in the generation of a small chemical library containing diterpenoid secondary metabolites with bioactivity in an infectious disease screening campaign focused on Leishmania donovani, Plasmodium falciparum, and methicillin-resistant Staphylococcus aureus (MRSA) biofilm. In total, eleven natural products were isolated, including three new compounds designated dendrillins B-D (10-12). Chemical modification of abundant natural products led to three semisynthetic derivatives (13-15), which were also screened. Several compounds showed potency against the leishmaniasis parasite, with the natural products tetrahydroaplysulphurin-1 (4) and dendrillin B (10), as well as the semisynthetic triol 15, displaying single-digit micromolar activity and low mammalian cytotoxicity. Triol 15 displayed the best profile against the liver-stage malaria parasites, while membranolide (5) and dendrillin C (11) were strong hits against MRSA biofilm cultures.


Asunto(s)
Antiinfecciosos/farmacocinética , Diterpenos/farmacología , Leishmania/efectos de los fármacos , Poríferos/química , Animales , Regiones Antárticas , Antiinfecciosos/química , Biopelículas , Productos Biológicos/aislamiento & purificación , Diterpenos/química , Hepatocitos , Humanos , Estructura Molecular , Plasmodium falciparum/efectos de los fármacos
13.
J Infect Dis ; 219(7): 1095-1103, 2019 03 15.
Artículo en Inglés | MEDLINE | ID: mdl-30358879

RESUMEN

Naegleria fowleri is the causative agent of primary amoebic meningoencephalitis (PAM), which is fatal in >97% of cases. In this study, we aimed to identify new, rapidly acting drugs to increase survival rates. We conducted phenotypic screens of libraries of Food and Drug Administration-approved compounds and the Medicines for Malaria Venture Pathogen Box and validated 14 hits (defined as a 50% inhibitory concentration of <1 µM). The hits were then prioritized by assessing the rate of action and efficacy in combination with current drugs used to treat PAM. Posaconazole was found to inhibit amoeba growth within the first 12 hours of exposure, which was faster than any currently used drug. In addition, posaconazole cured 33% of N. fowleri-infected mice at a dose of 20 mg/kg and, in combination with azithromycin, increased survival by an additional 20%. Fluconazole, which is currently used for PAM therapy, was ineffective in vitro and vivo. Our results suggest posaconazole could replace fluconazole in the treatment of PAM.


Asunto(s)
Antiprotozoarios/farmacología , Infecciones Protozoarias del Sistema Nervioso Central/tratamiento farmacológico , Descubrimiento de Drogas/métodos , Naegleria fowleri/efectos de los fármacos , Triazoles/farmacología , Anfotericina B/farmacología , Anfotericina B/uso terapéutico , Animales , Antiprotozoarios/uso terapéutico , Azitromicina/farmacología , Azitromicina/uso terapéutico , Modelos Animales de Enfermedad , Combinación de Medicamentos , Sinergismo Farmacológico , Femenino , Fluconazol/farmacología , Fluconazol/uso terapéutico , Humanos , Concentración 50 Inhibidora , Ratones , Fenotipo , Factores de Tiempo , Triazoles/uso terapéutico , Estados Unidos , United States Food and Drug Administration
14.
Blood ; 130(11): 1357-1363, 2017 09 14.
Artículo en Inglés | MEDLINE | ID: mdl-28698207

RESUMEN

Two malaria parasites of Southeast Asian macaques, Plasmodium knowlesi and P cynomolgi, can infect humans experimentally. In Malaysia, where both species are common, zoonotic knowlesi malaria has recently become dominant, and cases are recorded throughout the region. By contrast, to date, only a single case of naturally acquired P cynomolgi has been found in humans. In this study, we show that whereas P cynomolgi merozoites invade monkey red blood cells indiscriminately in vitro, in humans, they are restricted to reticulocytes expressing both transferrin receptor 1 (Trf1 or CD71) and the Duffy antigen/chemokine receptor (DARC or CD234). This likely contributes to the paucity of detectable zoonotic cynomolgi malaria. We further describe postinvasion morphologic and rheologic alterations in P cynomolgi-infected human reticulocytes that are strikingly similar to those observed for P vivax These observations stress the value of P cynomolgi as a model in the development of blood stage vaccines against vivax malaria.


Asunto(s)
Antígenos CD/metabolismo , Sistema del Grupo Sanguíneo Duffy/metabolismo , Plasmodium cynomolgi/fisiología , Receptores de Superficie Celular/metabolismo , Receptores de Transferrina/metabolismo , Reticulocitos/parasitología , Tropismo , Zoonosis/parasitología , Animales , Eritrocitos/parasitología , Interacciones Huésped-Parásitos , Humanos , Macaca , Merozoítos/fisiología , Plasmodium vivax/fisiología , Reología
15.
Artículo en Inglés | MEDLINE | ID: mdl-29311075

RESUMEN

Many organisms undergo dormancy as a stress response to survive under unfavorable conditions that might impede development. This is observed in seeds and buds of plants and has been proposed as a mechanism of drug evasion and resistance formation in Plasmodium falciparum We explored the effects of the phytohormones abscisic acid (ABA) and gibberellic acid (GA) on dihydroartemisinin (DHA)-induced dormant erythrocytic stages of P. falciparum parasites. Dormant ring stages exposed to ABA and GA recovered from dormancy up to 48 h earlier than parasites exposed to DHA alone. Conversely, fluridone, an herbicide inhibitor of ABA synthesis, blocked emergence from dormancy. Additionally, the role of the apicoplast was assessed in dormant parasite recovery. Apicoplast-deficient P. falciparum remained viable for up to 8 days without the organelle and recrudesced only when supplemented with isopentyl pyrophosphate (IPP). IPP was not required for survival in the dormant state. Fosmidomycin inhibition of isoprenoid biosynthesis did not prevent dormancy release from occurring in parasites with an intact apicoplast, but IPP or geranylgeranyl pyrophosphate was needed for complete recrudescence. In addition, the apicoplast and specifically the isoprenoids it produces are essential for recovery of dormant parasites. In summary, ABA and GA have significant effects on dormant parasites, and the phenotypes produced by these phytohormones and the herbicide fluridone also provide a means to explore the mechanism(s) underlying dormancy and the regulatory network that promotes cell cycle arrest in P. falciparum.


Asunto(s)
Apicoplastos/metabolismo , Artemisininas/farmacología , Reguladores del Crecimiento de las Plantas/farmacología , Plasmodium falciparum/efectos de los fármacos , Terpenos/farmacología , Ácido Abscísico/farmacología , Giberelinas/farmacología
16.
Artículo en Inglés | MEDLINE | ID: mdl-29941642

RESUMEN

Chloroquine-resistant (CQR) vivax malaria has emerged as a threat to the malaria elimination agenda. The objective of this study was to assess if a combination of chloroquine (CQ) and prochlorperazine was able to reverse CQ resistance of the Plasmodium vivax AMRU-1 strain from Papua New Guinea in infected Aotus monkeys. For this purpose, in two independent experimental drug efficacy trials, a total of 18 Aotus monkeys infected with blood obtained from donor animals were randomly assigned to treatment and control groups and orally administered CQ at 10 mg/kg or prochlorperazine at 20 mg/kg, alone or in combination, for five consecutive days. Reversal of CQR was achieved in animals that received the drug combination, whereas neither drug alone produced cures. This same drug combination reverses CQR in P. falciparum and could be an alternative for treatment in humans with chloroquine-resistant P. vivax infections.


Asunto(s)
Antimaláricos/farmacología , Cloroquina/farmacología , Haplorrinos/microbiología , Malaria Vivax/tratamiento farmacológico , Plasmodium vivax/efectos de los fármacos , Animales , Resistencia a Medicamentos/efectos de los fármacos , Femenino , Malaria Falciparum/tratamiento farmacológico , Malaria Vivax/microbiología , Masculino , Papúa Nueva Guinea , Plasmodium falciparum/efectos de los fármacos
17.
J Nat Prod ; 81(1): 117-123, 2018 01 26.
Artículo en Inglés | MEDLINE | ID: mdl-29260557

RESUMEN

During a 2013 cruise in the Southern Ocean we collected specimens of the octocoral Plumarella delicatissima between 800 and 950 m depth. Five new furanocembranoid diterpenes, keikipukalides A-E (1-5), the known diterpene pukalide aldehyde (6), and the known norditerpenoid ineleganolide (7) were isolated from the coral. These Plumarella terpenes lack mammalian cytotoxicity, while 2-7 display activity against Leishmania donovani between 1.9 and 12 µM. Structure elucidation was facilitated by one- and two-dimensional NMR spectroscopy and mass spectrometry, and keikipukalides A and E were confirmed by X-ray crystallography.


Asunto(s)
Antozoos/química , Diterpenos/química , Compuestos Macrocíclicos/química , Animales , Regiones Antárticas , Cristalografía por Rayos X/métodos , Diterpenos/aislamiento & purificación , Diterpenos/farmacología , Leishmania donovani/efectos de los fármacos , Compuestos Macrocíclicos/aislamiento & purificación , Compuestos Macrocíclicos/farmacología , Espectrometría de Masas/métodos , Resonancia Magnética Nuclear Biomolecular/métodos
18.
Mar Drugs ; 16(10)2018 Oct 10.
Artículo en Inglés | MEDLINE | ID: mdl-30308948

RESUMEN

There is an acute need for new and effective agents to treat infectious diseases. We conducted a screening program to assess the potential of mangrove-derived endophytic fungi as a source of new antibiotics. Fungi cultured in the presence and absence of small molecule epigenetic modulators were screened against Mycobacterium tuberculosis and the ESKAPE panel of bacterial pathogens, as well as two eukaryotic infective agents, Leishmania donovani and Naegleria fowleri. By comparison of bioactivity data among treatments and targets, trends became evident, such as the result that more than 60% of active extracts were revealed to be selective to a single target. Validating the technique of using small molecules to dysregulate secondary metabolite production pathways, nearly half (44%) of those fungi producing active extracts only did so following histone deacetylase inhibitory (HDACi) or DNA methyltransferase inhibitory (DNMTi) treatment.


Asunto(s)
Enfermedades Transmisibles/tratamiento farmacológico , Endófitos/metabolismo , Hongos/metabolismo , Animales , Antibacterianos/farmacología , Bacterias/efectos de los fármacos , Línea Celular , Descubrimiento de Drogas/métodos , Inhibidores de Histona Desacetilasas/farmacología , Metiltransferasas/antagonistas & inhibidores , Ratones
19.
Artículo en Inglés | MEDLINE | ID: mdl-28584157

RESUMEN

Malaria-related mortality has slowly decreased over the past decade; however, eradication of malaria requires the development of new antimalarial chemotherapies that target liver stages of the parasite and combat the emergence of drug resistance. The diminishing arsenal of anti-liver-stage compounds sparked our interest in reviving the old and previously abandoned compound menoctone. In support of these studies, we developed a new convergent synthesis method that was facile, required fewer steps, produced better yields, and utilized less expensive reagents than the previously published method. Menoctone proved to be highly potent against liver stages of Plasmodium berghei (50 percent inhibitory concentration [IC50] = 0.41 nM) and erythrocytic stages of Plasmodium falciparum (113 nM). We selected for resistance to menoctone and found M133I mutations in cytochrome b of both P. falciparum and P. berghei The same mutation has been observed previously in atovaquone resistance, and we confirmed cross-resistance between menoctone and atovaquone in vitro (for P. falciparum) and in vivo (for P. berghei). Finally, we assessed the transmission potential of menoctone-resistant P. berghei and found that the M133I mutant parasites were readily transmitted from mouse to mosquitoes and back to mice. In each step, the M133I mutation in cytochrome b, inducing menoctone resistance, was confirmed. In summary, this study is the first to show the mechanism of resistance to menoctone and that menoctone and atovaquone resistance is transmissible through mosquitoes.


Asunto(s)
Anopheles/parasitología , Antimaláricos/farmacología , Atovacuona/farmacología , Citocromos b/genética , Resistencia a Medicamentos/genética , Naftoquinonas/farmacología , Plasmodium berghei/genética , Plasmodium falciparum/genética , Animales , ADN Protozoario/genética , Femenino , Malaria Falciparum/tratamiento farmacológico , Malaria Falciparum/parasitología , Malaria Falciparum/transmisión , Ratones , Ratones Endogámicos BALB C , Mutación/genética , Plasmodium berghei/efectos de los fármacos , Plasmodium falciparum/efectos de los fármacos
20.
Artículo en Inglés | MEDLINE | ID: mdl-28533239

RESUMEN

High-grade chloroquine (CQ) resistance has emerged in both Plasmodium falciparum and P. vivax The aim of the present study was to investigate the phenotypic differences of CQ resistance in both of these species and the ability of known CQ resistance reversal agents (CQRRAs) to alter CQ susceptibility. Between April 2015 and April 2016, the potential of verapamil (VP), mibefradil (MF), L703,606 (L7), and primaquine (PQ) to reverse CQ resistance was assessed in 46 P. falciparum and 34 P. vivax clinical isolates in Papua, Indonesia, where CQ resistance is present in both species, using a modified schizont maturation assay. In P. falciparum, CQ 50% inhibitory concentrations (IC50s) were reduced when CQ was combined with VP (1.4-fold), MF (1.2-fold), L7 (4.2-fold), or PQ (1.8-fold). The degree of CQ resistance reversal in P. falciparum was highly correlated with CQ susceptibility for all CQRRAs (R2 = 0.951, 0.852, 0.962, and 0.901 for VP, MF, L7, and PQ, respectively), in line with observations in P. falciparum laboratory strains. In contrast, no reduction in the CQ IC50s was observed with any of the CQRRAs in P. vivax, even in those isolates with high chloroquine IC50s. The differential effect of CQRRAs in P. falciparum and P. vivax suggests significant differences in CQ kinetics and, potentially, the likely mechanism of CQ resistance between these two species.


Asunto(s)
Antimaláricos/farmacología , Cloroquina/farmacología , Resistencia a Medicamentos/fisiología , Malaria Falciparum/tratamiento farmacológico , Malaria Vivax/tratamiento farmacológico , Plasmodium falciparum/efectos de los fármacos , Plasmodium vivax/efectos de los fármacos , Humanos , Indonesia , Malaria Falciparum/parasitología , Malaria Vivax/parasitología , Pruebas de Sensibilidad Parasitaria , Plasmodium falciparum/aislamiento & purificación , Plasmodium vivax/aislamiento & purificación
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