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1.
Nat Commun ; 9(1): 22, 2018 01 02.
Artigo em Inglês | MEDLINE | ID: mdl-29295973

RESUMO

The public health threat posed by a looming 'post-antibiotic' era necessitates new approaches to antibiotic discovery. Drug development has typically avoided exploitation of membrane-binding properties, in contrast to nature's control of biological pathways via modulation of membrane-associated proteins and membrane lipid composition. Here, we describe the rejuvenation of the glycopeptide antibiotic vancomycin via selective targeting of bacterial membranes. Peptide libraries based on positively charged electrostatic effector sequences are ligated to N-terminal lipophilic membrane-insertive elements and then conjugated to vancomycin. These modified lipoglycopeptides, the 'vancapticins', possess enhanced membrane affinity and activity against methicillin-resistant Staphylococcus aureus (MRSA) and other Gram-positive bacteria, and retain activity against glycopeptide-resistant strains. Optimised antibiotics show in vivo efficacy in multiple models of bacterial infection. This membrane-targeting strategy has potential to 'revitalise' antibiotics that have lost effectiveness against recalcitrant bacteria, or enhance the activity of other intravenous-administered drugs that target membrane-associated receptors.


Assuntos
Antibacterianos/farmacologia , Bactérias/efeitos dos fármacos , Daptomicina/farmacologia , Farmacorresistência Bacteriana/efeitos dos fármacos , Proteínas de Membrana/metabolismo , Vancomicina/farmacologia , Animais , Antibacterianos/metabolismo , Antibacterianos/farmacocinética , Bactérias/classificação , Sobrevivência Celular/efeitos dos fármacos , Glicopeptídeos/metabolismo , Células HEK293 , Células Hep G2 , Humanos , Masculino , Staphylococcus aureus Resistente à Meticilina/efeitos dos fármacos , Camundongos , Testes de Sensibilidade Microbiana , Viabilidade Microbiana/efeitos dos fármacos , Staphylococcus aureus/efeitos dos fármacos
2.
Bioorg Med Chem Lett ; 22(7): 2428-33, 2012 Apr 01.
Artigo em Inglês | MEDLINE | ID: mdl-22406152

RESUMO

The rise of antibiotic resistance is of great clinical concern. One approach to reducing the development of resistance is to co-administer two or more antibiotics with different modes of action. However, it can be difficult to control the distribution and pharmacokinetics of two drugs to ensure both concentrations remain within the range of therapeutic efficacy whilst avoiding adverse effects. Hybrid drugs, where two drugs are linked together with a flexible linker, have been explored, but the resultant large, flexible molecules can have poor bioavailability. We have developed a chimeric approach using click chemistry where the pharmacophores of two drugs are overlapped into a single smaller, more drug-like molecule. Design and selection of compounds were assisted by in silico structural docking. We prepared a series of compounds that include candidates showing activity against the targets of both trimethoprim; dihydrofolate reductase, and ciprofloxacin; DNA gyrase and topoisomerase IV. The resultant triazole containing molecules show modest, but broad spectrum activities against drug sensitive and resistant Gram-negative and Gram-positive bacteria, with no observable cytotoxicity.


Assuntos
Antibacterianos/síntese química , Simulação por Computador , Antagonistas do Ácido Fólico/síntese química , Triazóis/síntese química , Antibacterianos/farmacologia , Ciprofloxacina/química , Química Click , DNA Girase/química , DNA Topoisomerase IV/antagonistas & inibidores , DNA Topoisomerase IV/química , Desenho de Fármacos , Resistência Microbiana a Medicamentos , Antagonistas do Ácido Fólico/farmacologia , Bactérias Gram-Negativas/efeitos dos fármacos , Bactérias Gram-Negativas/crescimento & desenvolvimento , Bactérias Gram-Positivas/efeitos dos fármacos , Bactérias Gram-Positivas/crescimento & desenvolvimento , Humanos , Testes de Sensibilidade Microbiana , Modelos Moleculares , Relação Estrutura-Atividade , Tetra-Hidrofolato Desidrogenase/química , Inibidores da Topoisomerase II , Triazóis/farmacologia , Trimetoprima/química
3.
J Org Chem ; 75(2): 491-4, 2010 Jan 15.
Artigo em Inglês | MEDLINE | ID: mdl-20000615

RESUMO

A convenient and high-yielding three-step synthesis of the simplest branched triene, [3]dendralene, has been devised. The synthesis is robust and operationally simple, requiring no chromatography and involving no protecting groups or specialized equipment, allowing the synthesis of the volatile hydrocarbon in pure, solvent free form on a multigram scale. The stability, dimerization when stored neat, and Diels-Alder reactivity of [3]dendralene--including double cycloaddition sequences and catalytic enantioselective variant--are reported.

4.
Org Lett ; 9(23): 4861-4, 2007 Nov 08.
Artigo em Inglês | MEDLINE | ID: mdl-17929828

RESUMO

The parent [3]dendralene and 2-substituted [3]dendralenes are made easily through cross-coupling reactions. Contrary to some earlier reports, [3]dendralene is sufficiently stable to be handled using standard synthetic methods. These compounds allow the one-step stereoselective construction of polycyclic frameworks through reactions with dienophiles. Site selectivity and stereoselectivity in Diels-Alder reactions with dienophiles are generally not influenced by the nature of the [3]dendralene's 2-substituent; these features can, however, be influenced with Lewis acids.

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