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Facing antibiotic resistance
Get PDFThe cell wall of most Gram-negative and Gram-positive bacteria is composed of peptidoglycan (PG), a mesh-like structure of repeating glycan chains cross-linked by small peptides. Peptidoglycan is essential for growth, division and viability of the microorganism. Any disruption of its biosynthesis results in bacterial cell lysis or cessation of growth, making it a major target for antibiotics.
It was suggested that many proteins involved in PG synthesis, from the cytoplasmic enzymes that synthesize the precursor Lipid II to the extracellular enzymes that are responsible for its polymerization, function in vivo as part of a multi- protein complex “machinery”. In particular, recent evidence suggests that the core of the PG biosynthetic complex consists of the class B penicillin binding proteins (PBPs) such as PBP2 and PBP3 that work together with membrane inserted shape, elongation, division and sporulation (SEDs) proteins, FtsW and RodA, respectively. These synthetic machines provide for cell division (FtsW-PBP3) and cell elongation (RodA-PBP2) and are also the key targets of most clinically used ß-lactam compounds.
Though structures of both RodA (a SEDS protein involved in bacterial growth and elongation) and type b PBPs are available, the interaction between these proteins and their joint enzymatic activity is poorly characterized.
Here, the preliminary structural characterization of a RodA-PBP2 protein complex by single-particle cryogenic electron microscopy (cryo-EM) is presented, aiming at a better understanding of these incredibly important enzymes that could enlighten the future of antibiotics research and development.The spread of multidrug resistance (MDR) Gram-negative bacterial pathogens and the paucity of new drugs prompted the medical community to re-use the old polymyxin antibiotic colistin.
Unfortunately, reintroduction of colistin in clinical practice led inevitably to the emergence of colistin-resistant isolates (Jeannot, K. et al. 2017), such as P. aeruginosa.
Gram-negative bacteria acquire colistin resistance mostly through mutations of genes responsible for remodeling of the lipopolysaccharide (LPS), primarily via the enzymatic addition of 4-amino-4-deoxy-L-arabinose (L-Ara4N) to lipid A by the aminoarabinose transferase ArnT. The resulting positive charge reduces LPS affinity for colistin, leading to resistance (Olaitan, A.O. et al., 2014; Baron, S. et al., 2016). Accordingly, the pharmacological inhibition of L-Ara4N biosynthetic pathway could represent a suitable approach to extend the clinical lifetime of colistin for the treatment of P. aeruginosa infections.
Here, in the attempt to identify potential inhibitors of L-Ara4N-dependent colistin resistance, a docking-based virtual screening of a unique in house library of natural products was carried out within the catalytic site of ArnT (Petrou, V.I. et al., 2016). This led to the identification of a natural diterpene (14) able to potentiate colistin activity against colistin-resistant P. aeruginosa isolates.
A series of semi-synthetic analogs were further synthesized and tested in vitro aiming at outlining the structure-activity relationship (SARs) and improving their activity. Currently, all these compounds are covered by Italian patent
Advances in the Synthesis of Bioactive Unnatural Amino Acids and Peptides
No full textThe key role of proteins and amino acids in the structure and function of living matter has stimulated extensive
studies. Modified amino acids with enhanced biological activity, proteolitic stability and bioavailability are of increasing
interest in protein design and engineering as drug candidates. In the last few years, several efforts have been devoted to
the synthesis of amino acids having unusual side chains and unnatural chirality, commonly referred to as
“nonproteinogenic” or “unnatural” amino acids, even though some of them can be isolated from natural sources. In this
review we describe recent advances in the amino acid side-chain transformations and backbone modifications by
oxidative and fluorination procedures
6-Substituted-4(3H)-pyrimidinones. A family of antiviral agents possessing a broad spectrum of activities
No full textOxidative strategies in lignin chemistry: a new approach for the functionalization of lignin wastes in biorefinery processes
No full textNovel processing methods and product concepts are required to extend the role of lignin for future
biomass and biofuel applications in emerging platforms such as the biorefinery. The possible strategies
of lignin valorisation are focused into two main directions, namely the selective functionalisation of the
lignin polymer or in its oxidative depolymerization to get polyfunctional monomeric compounds. Here
we report a panel of biocatalysis, organometallic catalysis, biomimetic catalysis and plasma oxidation
processes developed by our research group for the activation of the environmental friendly oxidants
oxygen and hydrogen peroxide in the oxidative functionalisation of lignin and lignin model compounds
Going Beyond Counting First Authors in Author Co-citation Analysis
Get PDFThe present study examines one of the fundamental aspects of author co-citation analysis (ACA) - the way co-citation
counts are defined. Co-citation counting provides the data on which all subsequent statistical analyses and mappings
are based, and we compare ACA results based on two different types of co-citation counting - the traditional type that
only counts the first one among a cited work's authors on the one hand and a non-traditional type that takes into
account the first 5 authors of a cited work on the other hand. Results indicate that the picture produced through this non-traditional author co-citation counting contains more coherent author groups and is therefore considerably clearer. However, this picture represents fewer specialties in the research field being studied than that produced through the traditional first-author co-citation counting when the same number of top-ranked authors is selected and analyzed. Reasons for these effects are discussed
Building a pharmacophore hypothesis for a class of potent and selective inhibitors of Parainfluenza 1 (Sendai) virus
No full text"Selective oxidation of phenol and anisole derivatives to quinones with hydrogen peroxide and polymer-supported methylrhenium trioxide systems."
No full textVariations on the Author
Get PDF“Variations on the Author” discusses two of Eduardo Coutinho’s recent films (Um Dia na Vida, from 2010, and Últimas Conversas, posthumously released in 2015) and their contribution to the general question of documentary authorship. The director’s filmography is characterized by a consistent yet self-effacing form of authorial self-inscription: Coutinho often features as an interviewer that rather than express opinions propels discourses; an interviewer that is good at listening. This mode of self-inscription characterizes him as an author who is not expressive but who is nonetheless markedly present on the screen. In Um Dia na Vida, however, Coutinho is completely absent form the image, while Últimas Conversas, on the contrary, includes a confessional prologue that moves the director from the margins to the center of his films. This article examines the ways in which these works stand out in the filmography of a director who offers new insights into the notion of cinematic authorship
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