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1.
Microbiol Spectr ; 11(6): e0274323, 2023 Dec 12.
Artículo en Inglés | MEDLINE | ID: mdl-37921483

RESUMEN

IMPORTANCE: The integration of metabolomics-based approaches into the discovery pipeline has enabled improved mining and prioritization of prolific secondary metabolite producers such as endophytic fungi. However, relying on automated untargeted analysis tools might lead to misestimation of the chemical complexity harbored in these organisms. Our study emphasizes the importance of isolation and structure elucidation of the respective metabolites in addition to deep metabolome analysis for the correct interpretation of untargeted metabolomics approaches such as molecular networking. Additionally, it encourages the further exploration of endophytic fungi from traditional medicinal plants for the discovery of natural products.


Asunto(s)
Plantas Medicinales , Policétidos , Endófitos , Lactonas/metabolismo , Policétidos/metabolismo , Metabolómica , Hongos/metabolismo
2.
EBioMedicine ; 73: 103652, 2021 Nov.
Artículo en Inglés | MEDLINE | ID: mdl-34740109

RESUMEN

BACKGROUND: The clinical-stage drug candidate EBL-1003 (apramycin) represents a distinct new subclass of aminoglycoside antibiotics for the treatment of drug-resistant infections. It has demonstrated best-in-class coverage of resistant isolates, and preclinical efficacy in lung infection models. However, preclinical evidence for its utility in other disease indications has yet to be provided. Here we studied the therapeutic potential of EBL-1003 in the treatment of complicated urinary tract infection and acute pyelonephritis (cUTI/AP). METHODS: A combination of data-base mining, antimicrobial susceptibility testing, time-kill experiments, and four murine infection models was used in a comprehensive assessment of the microbiological coverage and efficacy of EBL-1003 against Gram-negative uropathogens. The pharmacokinetics and renal toxicology of EBL-1003 in rats was studied to assess the therapeutic window of EBL-1003 in the treatment of cUTI/AP. FINDINGS: EBL-1003 demonstrated broad-spectrum activity and rapid multi-log CFU reduction against a phenotypic variety of bacterial uropathogens including aminoglycoside-resistant clinical isolates. The basicity of amines in the apramycin molecule suggested a higher increase in positive charge at urinary pH when compared to gentamicin or amikacin, resulting in sustained drug uptake and bactericidal activity, and consequently in potent efficacy in mouse infection models. Renal pharmacokinetics, biomarkers for toxicity, and kidney histopathology in adult rats all indicated a significantly lower nephrotoxicity of EBL-1003 than of gentamicin. INTERPRETATION: This study provides preclinical proof-of-concept for the efficacy of EBL-1003 in cUTI/AP. Similar efficacy but lower nephrotoxicity of EBL-1003 in comparison to gentamicin may thus translate into a higher safety margin and a wider therapeutic window in the treatment of cUTI/API. FUNDING: A full list of funding bodies that contributed to this study can be found in the Acknowledgements section.


Asunto(s)
Antibacterianos/uso terapéutico , Concentración de Iones de Hidrógeno , Nebramicina/análogos & derivados , Pielonefritis/tratamiento farmacológico , Infecciones Urinarias/tratamiento farmacológico , Animales , Antibacterianos/farmacología , Infecciones Bacterianas/tratamiento farmacológico , Infecciones Bacterianas/microbiología , Modelos Animales de Enfermedad , Relación Dosis-Respuesta a Droga , Farmacorresistencia Bacteriana Múltiple/efectos de los fármacos , Humanos , Ratones , Pruebas de Sensibilidad Microbiana , Nebramicina/farmacología , Nebramicina/uso terapéutico , Pielonefritis/etiología , Ratas , Resultado del Tratamiento , Infecciones Urinarias/etiología
3.
SLAS Discov ; 24(3): 398-413, 2019 03.
Artículo en Inglés | MEDLINE | ID: mdl-30616481

RESUMEN

Compound screening in biological assays and subsequent optimization of hits is indispensable for the development of new molecular research tools and drug candidates. To facilitate such discoveries, the European Research Infrastructure EU-OPENSCREEN was founded recently with the support of its member countries and the European Commission. Its distributed character harnesses complementary knowledge, expertise, and instrumentation in the discipline of chemical biology from 20 European partners, and its open working model ensures that academia and industry can readily access EU-OPENSCREEN's compound collection, equipment, and generated data. To demonstrate the power of this collaborative approach, this perspective article highlights recent projects from EU-OPENSCREEN partner institutions. These studies yielded (1) 2-aminoquinazolin-4(3 H)-ones as potential lead structures for new antimalarial drugs, (2) a novel lipodepsipeptide specifically inducing apoptosis in cells deficient for the pVHL tumor suppressor, (3) small-molecule-based ROCK inhibitors that induce definitive endoderm formation and can potentially be used for regenerative medicine, (4) potential pharmacological chaperones for inborn errors of metabolism and a familiar form of acute myeloid leukemia (AML), and (5) novel tankyrase inhibitors that entered a lead-to-candidate program. Collectively, these findings highlight the benefits of small-molecule screening, the plethora of assay designs, and the close connection between screening and medicinal chemistry within EU-OPENSCREEN.


Asunto(s)
Conducta Cooperativa , Descubrimiento de Drogas/métodos , Evaluación Preclínica de Medicamentos , Europa (Continente) , Ensayos Analíticos de Alto Rendimiento , Humanos , Relación Estructura-Actividad
4.
Angew Chem Int Ed Engl ; 56(28): 8272-8276, 2017 07 03.
Artículo en Inglés | MEDLINE | ID: mdl-28608939

RESUMEN

There is a strong need to better diagnose infections at deep body sites through noninvasive molecular imaging methods. Herein, we describe the synthesis and characterization of probes based on siderophore conjugates with catechol moieties and a central DOTAM scaffold. The probes can accommodate a metal ion as well as an antibiotic moiety and are therefore suited for theranostic purposes. The translocation of the conjugates across the outer and inner cell membranes of E. coli was confirmed by growth recovery experiments with enterobactin-deficient strains, by the antibacterial activity of ampicillin conjugates, and by confocal imaging using a fluorogen-activating protein-malachite green system adapted to E. coli. The suitability of the probes for in vivo imaging was demonstrated with a Cy5.5 conjugate in mice infected with P. aeruginosa.


Asunto(s)
Acetamidas/metabolismo , Infecciones por Escherichia coli/diagnóstico por imagen , Infecciones por Escherichia coli/tratamiento farmacológico , Compuestos Heterocíclicos con 1 Anillo/metabolismo , Infecciones por Pseudomonas/diagnóstico por imagen , Infecciones por Pseudomonas/tratamiento farmacológico , Sideróforos/metabolismo , Nanomedicina Teranóstica , Antibacterianos/uso terapéutico , Transporte Biológico , Endocitosis , Escherichia coli/metabolismo , Concentración 50 Inhibidora , Hierro/metabolismo , Pruebas de Sensibilidad Microbiana , Pseudomonas aeruginosa/metabolismo
5.
Science ; 348(6239): 1106-12, 2015 Jun 05.
Artículo en Inglés | MEDLINE | ID: mdl-26045430

RESUMEN

The discovery of Streptomyces-produced streptomycin founded the age of tuberculosis therapy. Despite the subsequent development of a curative regimen for this disease, tuberculosis remains a worldwide problem, and the emergence of multidrug-resistant Mycobacterium tuberculosis has prioritized the need for new drugs. Here we show that new optimized derivatives from Streptomyces-derived griselimycin are highly active against M. tuberculosis, both in vitro and in vivo, by inhibiting the DNA polymerase sliding clamp DnaN. We discovered that resistance to griselimycins, occurring at very low frequency, is associated with amplification of a chromosomal segment containing dnaN, as well as the ori site. Our results demonstrate that griselimycins have high translational potential for tuberculosis treatment, validate DnaN as an antimicrobial target, and capture the process of antibiotic pressure-induced gene amplification.


Asunto(s)
Antituberculosos/farmacología , Proteínas Bacterianas/antagonistas & inhibidores , Terapia Molecular Dirigida , Mycobacterium tuberculosis/efectos de los fármacos , Péptidos Cíclicos/farmacología , Tuberculosis Resistente a Múltiples Medicamentos/tratamiento farmacológico , Animales , Antituberculosos/química , Antituberculosos/uso terapéutico , Línea Celular Tumoral , Cristalografía por Rayos X , ADN Polimerasa Dirigida por ADN , Modelos Animales de Enfermedad , Diseño de Fármacos , Humanos , Ratones , Pruebas de Sensibilidad Microbiana , Datos de Secuencia Molecular , Mycobacterium smegmatis/efectos de los fármacos , Mycobacterium smegmatis/enzimología , Mycobacterium tuberculosis/enzimología , Péptidos Cíclicos/química , Péptidos Cíclicos/uso terapéutico , Estructura Secundaria de Proteína , Streptomyces/química , Streptomyces/efectos de los fármacos , Streptomyces/metabolismo , Tuberculosis Resistente a Múltiples Medicamentos/microbiología
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