Structure-antimicrobial activity of some natural isocoumarins and their analogues

Three naturally occurring isocoumarins (paepalantine, paepalantine 9-O-beta-D-glucopyranoside and paepalantine 90-beta-D-allopyranosyl(1 -> 6) glucopyranoside) and two semi-synthetic analogues, 9,10-acylated compound and 9-OH-10-methylated compound,. structurally similar to paepalantine, were evaluated for antimicrobial activity using a spectrophotometric microdilution technique. The paepalantine was active against S. aureus, S. epidermidis, and E faecalis. while the other four compounds proved ineffective against all microorganisms tested at concentrations of 500 mu g/ml. Variations in phenolic substitution at OH-9 and/or OH-10 in the paepalantine molecule resulted in compounds without antimicrobial activity. A combination of structural features, two phenolic groups as cathecolic system, forms an oxygenated system arrangement that may reflect the potentially antimicrobial properties of paepalantine. (c) 2004 Elsevier GmbH. All rights reserved.

In vitro antibacterial activity of medicinal plant extracts against Escherichia coli strains from human clinical specimens and interactions with antimicrobial drugs

Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)

Structure of BthA-I complexed with p-bromophenacyl bromide: possible correlations with lack of pharmacological activity

The crystal structure of an acidic phospholipase A(2) isolated from Bothrops jararacussu venom (BthA-I) chemically modified with p-bromophenacyl bromide (BPB) has been determined at 1.85 angstrom resolution. The catalytic, platelet-aggregation inhibition, anticoagulant and hypotensive activities of BthA-I are abolished by ligand binding. Electron-density maps permitted unambiguous identification of inhibitor covalently bound to His48 in the substrate-binding cleft. The BthA-I-BPB complex contains three structural regions that are modified after inhibitor binding: the Ca2+-binding loop, ss-wing and C-terminal regions. Comparison of BthA-I-BPB with two other BPB-inhibited PLA(2) structures suggests that in the absence of Na+ ions at the Ca2+- binding loop, this loop and other regions of the PLA(2)s undergo structural changes. The BthA-I-BPB structure reveals a novel oligomeric conformation. This conformation is more energetically and conformationally stable than the native structure and the abolition of pharmacological activities by the ligand may be related to the oligomeric structural changes. A residue of the `pancreatic' loop (Lys69), which is usually attributed as providing the anticoagulant effect, is in the dimeric interface of BthA-I-BPB, leading to a new hypothesis regarding the abolition of this activity by BPB.

Crystal structure of a myotoxic Asp49-phospholipase A(2) with low catalytic activity: Insights into Ca2+ -independent catalytic mechanism

A myotoxic Asp49-phospholipase A(2) (Asp49-PLA(2)) with low catalytic activity (BthTX-II from Bothrops jararacussu venom) was crystallized and the molecular-replacement solution has been obtained with a dimer in the asymmetric unit. The quaternary structure of BthTX-II resembles the myotoxic Asp49-PLA2 PrTX-III (piratoxin III from B. pirajai venom) and all non-catalytic and myotoxic dimeric Lys49-PLA(2)s. Despite of this, BthTX-II is different from the highly catalytic and non-myotoxic BthA-I (acidic PLA(2) from B. jararacussu) and other Asp49-PLA(2)s. BthTX-II structure showed a severe distortion of calcium-binding loop leading to displacement of the C-terminal region. Tyr28 side chain, present in this region, is in an opposite position in relation to the same residue in the catalytic activity Asp49-PLA(2)s, making a hydrogen bond with the atom 0 delta 2 of the catalytically active Asp49, which should coordinate the calcium. This high distortion may also be confirmed by the inability of BthTX-II to bind Na+ ions at the Ca2+-binding loop, despite of the crystallization to have occurred in the presence of this ion. In contrast, other Asp49-PLA(2)s which are able to bind Ca2+ ions are also able to bind Na+ ions at this loop. The comparison with other catalytic, non-catalytic and inhibited PLA(2)s indicates that the BthTX-II is not able to bind calcium ions; consequently, we suggest that its low catalytic function is based on an alternative way compared with other PLA(2)s. (c) 2008 Elsevier B.V All rights reserved.

Crystal structure of a phospholipase A(2) homolog complexed with p-bromophenacyl bromide reveals important structural changes associated with the inhibition of myotoxic activity

Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)

Anti-coagulase-negative Staphylococcus activity of ethanolic extracts of propolis from two Brazilian regions and synergism with antimicrobial drugs by the E-test method

Propolis is a natural resinous substance collected by bees from vegetal sources and its therapeutic properties have been investigated. In this work, we evaluated the inhibitory activity of ethanolic extracts of propolis (EEP) from the Southeast and South of Brazil on coagulase-negative Staphylococcus (CNS) growth as well as the EEP in vitro synergism with antimicrobial drugs by using the diffusion method (E-test). The EEP chemical characteristics (dry weight, pH, flavonoid and phenolic compounds) were determined. Seven drugs were tested, and synergism was observed between three drugs and Southeast EEP, six drugs and South EEP, and one drug and ethanol control. Ethanolic extracts of propolis from the South of Brazil presented the greatest flavonoid content and synergism rate, while EEP from the Southeast presented the greatest anti-CNS activity and phenolic compound content. Results showed the correlation among anti-CNS activity, synergism rate and chemical characteristics of propolis.

Interfacial surface charge and free accessibility to the PLA(2)-active site-like region are essential requirements for the activity of Lys49 PLA(2) homologues

Lys49 phospholipase A(2) homologues are highly myotoxic and cause extensive tissue damage but do not display hydrolytic activity towards natural phospholipids. The binding of heparin, heparin derivatives and polyanionic compounds such as suramin result in partial inhibition (up to 60%) of the myotoxic effects due to a change in the overall charge of the interfacial surface. In vivo experiments demonstrate that polyethylene glycol inhibits more than 90% of the myotoxic effects without exhibiting secondary toxic effects. The crystal structure of bothropstoxin-I complexed with polyethylene glycol reveals that this inhibition is due to steric hindrance of the access to the PLA(2)-active site-like region. These two inhibitory pathways indicate the roles of the overall surface charge and free accessibility to the PLA2-active site-like region in the functioning of Lys49 phospholipases A(2) homologues. Molecular dynamics simulations, small angle X-ray scattering and structural analysis indicate that the oligomeric states both in solution and in the crystalline states of Lys49 phospholipases A2 are principally mediated by hydrophobic contacts formed between the interfacial surfaces. These results provide the framework for the potential application of both clinically approved drugs for the treatment of Viperidae snakebites. (c) 2006 Elsevier Ltd. All rights reserved.

Crystal structure of a dimeric Ser49 PLA(2)-like myotoxic component of the Vipera ammodytes meridionalis venomics reveals determinants of myotoxicity and membrane damaging activity

Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES)

Structural basis for branching-enzyme activity of glycoside hydrolase family 57: Structure and stability studies of a novel branching enzyme from the hyperthermophilic archaeon Thermococcus Kodakaraensis KOD1

Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)

Enzymatic Activity, Sensitivity to Antifungal Drugs and Baccharis dracunculifolia Essential Oil by Candida Strains Isolated from the Oral Cavities of Breastfeeding Infants and in Their Mothers' Mouths and Nipples

Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)

Effects of Dimerization on the Structure and Biological Activity of Antimicrobial Peptide Ctx-Ha

Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq)

Influence of N-Terminus Modifications on the Biological Activity, Membrane Interaction, and Secondary Structure of the Antimicrobial Peptide Hylin-a1

Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)

Surface structure and electronic properties of Pt-Fe/C nanocatalysts and their relation with catalytic activity for oxygen reduction

Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)