STUDY OBJECTIVE\nWe sought to determine the prevalence of methicillin-resistant Staphylococcus aureus (MRSA) among emergency department (ED) patients with skin and soft tissue infections, identify demographic and clinical variables associated with MRSA, and characterize MRSA by antimicrobial susceptibility and genotype.\n\n\nMETHODS\nThis was a prospective observational study involving a convenience sample of patients who presented with skin and soft tissue infections to a single urban public hospital ED in California. Nares and infection site cultures were obtained. A health and lifestyle questionnaire was administered, and predictor variables independently associated with MRSA were determined by multivariate logistic regression. All S aureus isolates underwent antibiotic susceptibility testing. Eighty-five MRSA isolates underwent genotyping by pulsed field gel electrophoresis, staphylococcal chromosomal cassette mec (SCC mec ) typing, and testing for Panton-Valentine leukocidin genes.\n\n\nRESULTS\nOf 137 subjects, 18% were homeless, 28% injected illicit drugs, 63% presented with a deep or superficial abscess, and 26% required admission for the infection. MRSA was present in 51% of infection site cultures. Of 119 S aureus isolates (from infection site and nares), 89 (75%) were MRSA. Antimicrobial susceptibility among MRSA isolates was trimethoprim/sulfamethoxazole 100%, clindamycin 94%, tetracycline 86%, and levofloxacin 57%. Among predictor variables independently associated with MRSA infection, the strongest was infection type being furuncle (odds ratio 28.6). Seventy-six percent of MRSA cases fit the clinical definition of community associated. Ninety-nine percent of MRSA isolates possessed the SCC mec IV allele (typical of community-associated MRSA), 94.1% possessed Panton-Valentine leukocidin genes, and 87.1% belonged to a single clonal group (ST8:S).\n\n\nCONCLUSION\nIn this urban ED population, MRSA is a major pathogen in skin and soft tissue infections. Although studies from other practice settings are needed, MRSA should be considered when empiric antibiotic therapy is selected for such infections.

High Prevalence of Methicillin-resistant Staphylococcus aureus (MRSA) in Emergency Department Skin and Soft-tissue Infections

The review lays emphasis on the significance of 1,2,3-triazoles synthesized via CuAAC reaction having potential to act as anti-microbial, anti-cancer, anti-viral, anti-inflammatory, anti-tuberculosis, anti-diabetic, and anti-Alzheimer drugs. The importance of click chemistry is due to its ‘quicker’ methodology that has the capability to create complex and efficient drugs with high yield and purity from simple and cheap starting materials. The activity of different triazolyl compounds was compiled considering MIC, IC50, and EC50 values against different species of microbes. In addition to this, the anti-oxidant property of triazolyl compounds have also been reviewed and discussed.

https://pubs.rsc.org/en/content/articlepdf/2020/RA/C9RA09510A

CuAAC-ensembled 1,2,3-triazole-linked isosteres as pharmacophores in drug discovery: review

Fluoroquinolones remain one of the most important kind of antibacterial agents used nowadays. The emergence of more virulent and resistant strains of bacteria by the development of either mutated DNA-binding proteins or efflux pump mechanism for drugs is considered the main problem associated with the therapeutic use of these drugs. This situation participated in pushing researchers to design new fluoroquinolone derivatives, mainly with different substituents at C-7 to withstand these resistant strains of bacteria and to obtain a wider spectrum of activity including activity against anaerobic organisms. Conjugation of fluoroquinolones with substitutions such as 1,2,4-triazoles, alkyl oximes, flavonoids, aryl furans, benzofuroxans, metronidazoles or even other antibiotics such as neomycin-B produced derivatives that have a superior and wider spectrum of activity and better resistance than the classical fluoroquinolone agents. Addition of a hydroxamic acid moiety to fluoroquinolones also increased the activity against Proteus mirabilis, which represents one of the most resistant strains of bacteria in urinary tract infections. This review aims to highlight the recent updates made for fluoroquinolones for broadening the spectrum of activity to become active not only against resistant strains of bacteria but also against anaerobic pathogens.

Recent updates of fluoroquinolones as antibacterial agents.

Antibacterial activities with the structure-activity relationship of coumarin derivatives

Vancomycin has been the most reliable therapeutic agent against infections caused by meticillin-resistant Staphylococcus aureus (MRSA). However, in 1996 the first MRSA to acquire resistance to vancomycin, was isolated from a Japanese patient. The patient had contracted a post-operative wound infection that was refractory to long-term vancomycin therapy. Subsequent isolation of several vancomycin resistant S. aureus (VRSA) strains from USA, France, Korea, South Africa, and Brazil has confirmed that emergence of vancomycin resistance in S aureus is a global issue. A certain group of S. aureus, designated hetero-VRSA, frequently generate VRSA upon exposure to vancomycin, and are associated with infections that are potentially refractory to vancomycin therapy. Presence of hetero-VRSA may be an important indicator of the insidious decline of the clinical effectiveness of vancomycin in the hospitals. Vancomycin resistance is acquired by mutation and thickening of cell wall due to accumulation of excess amounts of peptidoglycan. This seems to be a common resistance mechanism for all VRSA strains isolated in the world so far.

Iconographies supplémentaires de l'article : Vancomycin-resistant Staphylococcus aureus : a new model of antibiotic resistance

A new series of coumarin-1,2,3-triazole conjugates with varied alkyl, phenyl and heterocycle moieties at C-4 of the triazole nucleus were synthesized using a copper(I)-catalysed Huisgen 1,3-dipolar cycloaddition reaction of corresponding O-propargylated coumarin (3) or N-propargylated coumarin (6) with alkyl or aryl azides. Based on their minimal inhibitory concentrations (MICs) against selected microorganisms, six out of twenty-six compounds showed significant antibacterial activity towards Enterococcus faecalis (MIC = 12.5–50 µg/mL). Moreover, the synthesized triazoles show relatively low toxicity against human erythrocytes.

https://www.mdpi.com/1420-3049/23/1/199/pdf

Synthesis and Antimicrobial Activity of 4-Substituted 1,2,3-Triazole-Coumarin Derivatives

A series of 34 1,2,3-triazole-naphthoquinone conjugates were synthesized via copper-catalyzed cycloaddition (CuAAC). They were evaluated for their in vitro antimalarial activity against chloroquine-sensitive strains of Plasmodium falciparum and against three different tumor cell lines (SKBr-3, MCF-7, HEL). The most active antimalarial compounds showed a low antiproliferative activity. Simplified analogues were also obtained and some structure–activity relationships were outlined. The best activity was obtained by compounds 3s and 3j, having IC50 of 0.8 and 1.2 μM, respectively. Molecular dockings were also carried on Plasmodium falciparum enzyme dihydroorotate dehydrogenase (PfDHODH) in order to rationalize the results.

Synthesis and Antiplasmodial Activity of 1,2,3-Triazole-Naphthoquinone Conjugates.

Based on molecular docking studies on the ERα, a series of lignan derivatives (3–16) were designed and semisynthesized from the natural dibenzylbutyrolactones bursehernin (1) and matairesinol dimethyl ether (2). To examine their estrogenic and antiestrogenic potencies, the effects of these compounds on estrogen receptor element (ERE)-driven reporter gene expression and viability in human ER+ breast cancer cells were evaluated. Lignan compounds induced ERE-driven reporter gene expression with very low potency as compared with the pure agonist E2. However, coincubation of 5 μM of lignan derivatives 1, 3, 4, 7, 8, 9, 11, 13, and 14 with increasing concentrations of E2 (from 0.01 pM to 1 nM) reduced both the potency and efficacy of pure agonists. The binding to the rhERα-LBD was validated by TR-FRET competitive binding assay and lignans bound to the rhERα with IC50 values from 0.16 μM (compound 14) to 6 μM (compound 4). Induced fit docking (IFD) and molecular dynamics (MD) simulations for compound 14 were carried out to further investigate the binding mode interactions. Finally, the in silico ADME predictions indicated that the most potent lignan derivatives exhibited good drug-likeness.

/pdf/design-semisynthesis-and-estrogenic-activity-of-lignan-2wu9pyqg.pdf

Design, Semisynthesis, and Estrogenic Activity of Lignan Derivatives from Natural Dibenzylbutyrolactones

Synthesis and biological evaluation of anthracene-9,10 dione derivatives as CK2 inhibitors

Simple Summary About 70% of the breast tumors diagnosed are estrogen receptor (ER)-positive and depend on estrogens and the interactions with their ER to grow and survive; their therapeutic treatment has a good clinical prognosis and effectiveness, but antitumoral treatment resistances and undesirable side effects (ovarian cysts, endometrial cancer, or blood clots) remain clinically challenging. This justifies the development of new drugs that modulate ER activity since it is considered a clinically validated therapeutic target. The goal of this study was the identification and the preclinical pharmacological evaluation of new structures with antitumoral and/or antiestrogenic properties with alternative or complementary mechanisms of action to the endocrine therapy used in the gold-standard treatment of ER-positive breast cancer. Thus, we identified two leading compounds (highly-functionalized 5-hydroxy-2H-pyrrol-2-ones) with potential antitumoral effects and scarce estrogenic activity, which offers a pharmacological opportunity to progress in the study of ER-positive breast cancer treatment. Abstract Tamoxifen improves the overall survival rate in hormone receptor-positive breast cancer patients. However, despite the fact that it exerts antagonistic effects on the ERα, it can act as a partial agonist, resulting in tumor growth in estrogen-sensitive tissues. In this study, highly functionalized 5-hydroxy-2H-pyrrol-2-ones were synthesized and evaluated by using ERα- and phenotype-based screening assays. Compounds 32 and 35 inhibited 17β-estradiol (E2)-stimulated ERα-mediated transcription of the luciferase reporter gene in breast cancer cells without inhibition of the transcriptional activity mediated by androgen or glucocorticoid receptors. Compound 32 regulated E2-stimulated ERα-mediated transcription by partial antagonism, whereas compound 35 caused rapid and non-competitive inhibition. Monitoring of 2D and 3D cell growth confirmed potent antitumoral effects of both compounds on ER-positive breast cancer cells. Furthermore, compounds 32 and 35 caused apoptosis and blocked the cell cycle of ER-positive breast cancer cells in the sub-G1 and G0/G1 phases. Interestingly, compound 35 suppressed the functional activity of ERα in the uterus, as demonstrated by the inhibition of E2-stimulated transcription of estrogen and progesterone receptors and alkaline phosphatase enzymatic activity. Compound 35 showed a relatively low binding affinity with ERα. However, its antiestrogenic effect was associated with an increased polyubiquitination and a reduced protein expression of ERα. Clinically relevant, a possible combinatory therapy with compound 35 may enhance the antitumoral efficacy of 4-hydroxy-tamoxifen in ER-positive breast cancer cells. In silico ADME predictions indicated that these compounds exhibit good drug-likeness, which, together with their potential antitumoral effects and their lack of estrogenic activity, offers a pharmacological opportunity to deepen the study of ER-positive breast cancer treatment.

/pdf/discovery-of-highly-functionalized-5-hydroxy-2h-pyrrol-2-2retslma.pdf

Discovery of Highly Functionalized 5-hydroxy-2H-pyrrol-2-ones That Exhibit Antiestrogenic Effects in Breast and Endometrial Cancer Cells and Potentiate the Antitumoral Effect of Tamoxifen

Priscila López-Rojas

Papers

Synthesis and Antimicrobial Activity of 4-Substituted 1,2,3-Triazole-Coumarin Derivatives

Synthesis and Antiplasmodial Activity of 1,2,3-Triazole-Naphthoquinone Conjugates.

Design, Semisynthesis, and Estrogenic Activity of Lignan Derivatives from Natural Dibenzylbutyrolactones

Synthesis and biological evaluation of anthracene-9,10 dione derivatives as CK2 inhibitors

Discovery of Highly Functionalized 5-hydroxy-2H-pyrrol-2-ones That Exhibit Antiestrogenic Effects in Breast and Endometrial Cancer Cells and Potentiate the Antitumoral Effect of Tamoxifen