[Show abstract][Hide abstract] ABSTRACT: A series of indole sesquiterpenes analogues of polyalthenol and pentacyclindole have been synthesized starting from ent-halimic acid in order to test their biological activity. These analogues include diverse oxidation levels at the sesquiterpenyl moiety and different functionalization on the indole ring. All synthetic derivatives were tested against a representative panel of Gram positive and Gram negative bacterial strains, and the human solid tumour cell lines A549 (non-small cell lung), HBL-100 (breast), HeLa (cervix), SW1573 (non-small cell lung), T-47D (breast) and WiDr (colon). Overall, the compounds presented activity against the cancer cell lines. The resulting lead, displaying a polyalthenol scaffold, showed GI50 values in the range 1.2-5.7 μM against all cell lines tested.
European Journal of Medicinal Chemistry 12/2013; 73C:265-279. DOI:10.1016/j.ejmech.2013.12.012 · 3.45 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Mupirocin is used for the decolonization of methicillin-resistant Staphylococcus aureus (MRSA). High-level mupirocin resistance (Hi-Mup(R)) is of concern, having been associated with therapeutic failure. Our main objective was to assess the emergence and mode/s of spread of Hi-Mup(R) in the MRSA population recovered between 2002 and 2009 in four health care settings in the Pontevedra province, northwest Spain. Five hundred and fifty consecutive clinical MRSA isolates were obtained and screened for antimicrobial susceptibility. Isolates were stratified into multidrug-resistant (MDR) and non-MDR. High-level mupirocin resistant MRSA were characterized by genotyping and plasmid analysis. Thirty-one MRSA (5.6%) exhibited Hi-Mup(R). No association was detected between Hi-Mup(R) and MDR but isolates displaying Hi-Mup(R) were more likely to be resistant to gentamicin and tobramycin. Four main MRSA clones were identified: ST125/t067/PFGE A, ST36/t018/PFGE D, ST8/t008/PFGE B, and ST72/t148 or t3092/PFGE B. Each isolate carried the Hi-Mup(R)ileS2-encoding gene on plasmids and ten plasmid types were distinguished based on unique IS257-ileS2 configurations. Some plasmid types were successfully disseminated among the MRSA clones. Remarkably, six plasmid types were acquired by the predominant genotype ST125/t067/PFGE A. In conclusion, molecular characterization of MRSA isolates combined with the rapid typing of ileS2-encoding plasmids through determination of IS257-ileS2 configurations have proved to be a powerful strategy to address the molecular epidemiology of Hi-Mup(R). The transmission of a diverse set of ileS2-carrying plasmids promoted the emergence of the resistance, with a limited role of clonal expansion in its dispersion.
International journal of medical microbiology: IJMM 03/2013; 303(4). DOI:10.1016/j.ijmm.2013.03.003 · 3.61 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: The genetic analysis of high-level mupirocin resistance (Hi-Mup(R)) in a Staphylococcus pseudintermedius isolate from a dog was presented. The Hi-Mup(R) ileS2 gene flanked by a novel rearrangement of directly repeated insertion sequence IS257 elements was located, together with the aminoglycoside resistance aacA-aphD determinant, on a conjugative plasmid related to the pSK41/pGO1 family plasmids.
[Show abstract][Hide abstract] ABSTRACT: Background
Despite our increased understanding of the mechanisms involved in acute lung injury (ALI) and the acute respiratory distress syndrome (ARDS), there is no specific pharmacological treatment of proven benefit. We used a novel screening methodology to examine potential anti-inflammatory effects of a small structure-focused library of synthetic carbamate and urea derivatives in a well established cell model of lipopolysaccharide (LPS)-induced ALI/ARDS.
After a pilot study to develop an in vitro LPS-induced airway epithelial cell injury model, a library of synthetic carbamate and urea derivates was screened against representative panels of human solid tumor cell lines and bacterial and fungal strains. Molecules that were non-cytotoxic and were inactive in terms of antiproliferative and antimicrobial activities were selected to study the effects on LPS-induced inflammatory response in an in vitro cell culture model using A549 human alveolar and BEAS-2B human bronchial cells. These cells were exposed for 18 h to LPS obtained from Escherichia coli, either alone or in combination with the test compounds. The LPS antagonists rhein and emodin were used as reference compounds. The most active compound (CKT0103) was selected as the lead compound and the impact of CKT0103 on pro-inflammatory IL-6 and IL-8 cytokine levels, expression of toll-like receptor-4 (TLR4) and nuclear factor kappa B inhibitor alpha (IκBα) was measured. CKT0103 significantly inhibited the synthesis and release of IL-6 and IL-8 induced by LPS. This suppression was associated with inhibition of TLR4 up-regulation and IκBα down-regulation. Immunocytochemical staining for TLR4 and IκBα supported these findings.
Using a novel screening methodology, we identified a compound – CKT0103 – with potent anti-inflammatory effects. These findings suggest that CKT0103 is a potential target for the treatment of the acute phase of sepsis and sepsis-induced ALI/ARDS.
PLoS ONE 11/2012; 7(11):e48468. DOI:10.1371/journal.pone.0048468 · 3.23 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: In this study, we synthesized a series of phenylpropanoic acid derivatives based on modifications at four selected points of the molecular scaffold. The in vitro antiproliferative activities of the compounds were examined in representative human solid tumor cell lines. A SAR was established pointing out the relevance of the substituents. The best activity profiles were obtained for the derivatives bearing more lipophilic esters (GI50 3.1-21 microM).
[Show abstract][Hide abstract] ABSTRACT: The biological evaluation of new Ru(II) complexes carrying dmoPTA (dmoPTA=3,7-dimethyl-1,3,7-triaza-5-phosphabicyclo[3.3.1]nonane) ligands is reported. The results on the biological activity revealed that the organometallic complexes are active against all cell lines with GI(50) values in the range 1.1-2.6 μM. When compared to the standard anticancer drug cisplatin, the bimetallic Ru(II) complexes showed a greater activity profile. The cell cycle analysis revealed that the new compounds induced arrest in G(1) phase. Contrary to cisplatin, these Ru(II) complexes do not interact with DNA. This result suggests that DNA might not be the key pharmacological target.
[Show abstract][Hide abstract] ABSTRACT: Plasmids encoding the ileS2 gene are responsible for the wide spread of high-level mupirocin resistance in staphylococci, and consequent clinical and epidemiological problems. We investigated the location of insertion sequence IS257 flanking ileS2 in different plasmids and developed a method for molecular typing of the IS257-ileS2 spacer regions.
Nine ileS2-encoding plasmids (i.e. pPR1-pPR9) classified into distinct structural groups (i.e. S1-S4) were analysed. Complete DNA sequences between IS257s flanking ileS2 were determined. A PCR-based amplification scheme was designed for the simultaneous amplification of up- and down-stream IS257-ileS2 regions. The method was applied to a total of 90 high-level mupirocin-resistant clinical isolates of methicillin-resistant Staphylococcus aureus (MRSA).
pPR1-pPR9 possessed IS257s flanking ileS2. Plasmids of each structural group showed a unique configuration of IS257-ileS2 spacer regions. The PCR-based method permitted accurate typing of the heterogeneous IS257-ileS2 up- and down-stream junctions, and the differentiation of plasmids of each group. The results obtained corresponded with previous plasmid typing based on restriction enzyme analyses and ileS2 locus hybridization polymorphs. The application of the PCR-based method to a diverse collection of MRSA isolates carrying ileS2-encoding plasmids demonstrated its versatility and revealed extraordinary heterogeneity in the IS257-ileS2 spacers.
The devised PCR-based scheme offers a rapid, simple and effective approach for typing IS257-ileS2 configurations present on ileS2-encoding plasmids. Hopefully, it could serve as a useful molecular epidemiological tool to control high-level mupirocin resistance.
[Show abstract][Hide abstract] ABSTRACT: Multiple-locus variable-number tandem-repeat analysis (MLVA) was performed with 292 methicillin-resistant Staphylococcus aureus (MRSA) isolates previously characterized by pulsed-field gel electrophoresis, multilocus sequence typing, and staphylococcal
cassette chromosome mec typing. Quantitative correspondence analyses showed the best correlation between data when an ≥80% cutoff was applied to
MLVA. We confirmed the validity of MLVA for identification of related strains in a polyclonal MRSA population.
[Show abstract][Hide abstract] ABSTRACT: ChemInform is a weekly Abstracting Service, delivering concise information at a glance that was extracted from about 100 leading journals. To access a ChemInform Abstract of an article which was published elsewhere, please select a “Full Text” option. The original article is trackable via the “References” option.
[Show abstract][Hide abstract] ABSTRACT: A small structure-focused library of propargylic enol ethers was prepared by means of a modular and efficient chemodifferentiating organocatalyzed multicomponent reaction. The most active compound (GI(50) 0.25 microM) against solid tumor cells was selected as lead. Cell cycle analysis and immunoblotting demonstrated arrest at the metaphase, pointing out human topoisomerase II as plausible molecular target. In vitro assays were carried out, showing that the lead behaves as a catalytic inhibitor of the enzyme.
[Show abstract][Hide abstract] ABSTRACT: A series of 2-substituted 1,2-dihydro-3-phenyl-1-(trichloromethyl)benzo[b][1,6]naphthyridines were synthesized and their in vitro antiproliferative activities were examined against human solid tumor cell lines and relevant strains of bacteria and Candida. The compounds induced considerably growth inhibition in all cancer cell lines, whilst showed inactive against microbial strains. Furthermore, we found analog 2-ethoxy-1H-pyrano[4,3-b]quinoline as selective inhibitor of microbial strains.
[Show abstract][Hide abstract] ABSTRACT: We have sequenced the conjugative plasmid pPR9, which carries the ileS2 gene, which had contributed to the dissemination of high-level mupirocin resistance at our institution. The plasmid backbone shows extensive genetic conservation with plasmids belonging to the pSK41/pGO1 family, but comparative analyses have revealed key differences that provide important insights into the evolution of these medically important plasmids and high-level mupirocin resistance in staphylococci and highlight the role of insertion sequence IS257 in these processes.
[Show abstract][Hide abstract] ABSTRACT: Panton-Valentine leukocidin (PVL) is associated with staphylococcal skin and pulmonary infections. Community dissemination
of PVL-producing Staphylococcus aureus strains constitutes a public health concern. Family transmission and spread of community-acquired leukocidin-positive methicillin-susceptible
S. aureus ST152 isolates associated with severe clinical symptoms are herein described. Remarkably, ST152 isolates usually are methicillin