How educators can engage male service providers in the prevention of violence against women : strategies and activities

The overall purpose of my Masters of Education (Counselling) project was to create innovative, theory-based strategies and activities that educators (e.g., professors, teachers, and educators who work with agencies dedicated to ending violence against women and creating violence-free communities) can use with male service providers (e.g., therapists, coaches, nurses) to facilitate change in their personal and professional environments with regards to ending violence against women. Educators can use these strategies and activities in delivering courses, training seminars, and capacity building workshops meant to deconstruct male socialization and engage men in the prevention of violence against women. My intention in the development of these strategies was to fill a gap in the research about how male providers can influence individual, interpersonal, and social change in connection to violence against women. This project is comprised of two parts. The first will include a detailed literature view pertaining to the synthesis and development of theory-based strategies that educators can incorporate in their work to engage male providers in preventing violence against women in their personal and professional lives. The second aspect of the project is a manuscript detailing these strategies to be submitted to a peer-reviewed journal for the targeted audience to access

Mucin binding reduces colistin antimicrobial activity

Colistin has found increasing use in treating drug-resistant bacterial lung infections, but potential interactions with pulmonary biomolecules have not been investigated. We postulated that colistin, like aminoglycoside antibiotics, may bind to secretory mucin in sputum or epithelial mucin that lines airways, reducing free drug levels. To test this hypothesis, we measured binding of colistin and other antibiotics to porcine mucin, a family of densely glycosylated proteins used as a surrogate for human sputum and airway mucin. Antibiotics were incubated in dialysis tubing with or without mucin, and concentrations of unbound antibiotics able to penetrate the dialysis tubing were measured over time using liquid chromatography-tandem mass spectrometry (LC-MS/MS). The percentage of antibiotic measured in the dialysate after 4 h in the presence of mucin, relative to the amount without mucin, was 15% for colistin, 16% for polymyxin B, 19% for tobramycin, 52% for ciprofloxacin, and 78% for daptomycin. Antibiotics with the strongest mucin binding had an overall polybasic positive charge, whereas those with comparatively little binding were less basic. When comparing MICs measured with or without added mucin, colistin and polymyxin B showed >100-fold increases in MICs for multiple Gram-negative bacteria. Preclinical evaluation of mucin binding should become a standard procedure when considering the potential pulmonary use of new or existing antibiotics, particularly those with a polybasic overall charge. In the airways, mucin binding may reduce the antibacterial efficacy of inhaled or intravenously administered colistin, and the presence of sub-MIC effective antibiotic concentrations could result in the development of antibiotic resistance

Institutional profile: Community for Open Antimicrobial Drug Discovery – crowdsourcing new antibiotics and antifungals

The Community for Open Antimicrobial Drug Discovery (CO-ADD) is a not-for-profit, collaborative approach to discovering new antibiotics. We access novel chemical diversity from academic synthetic chemists, who collectively possess millions of untested compounds with chemical diversity that lie outside commercial collections. We perform high-throughput antimicrobial screening of pure compounds derived from both synthetic and natural sources free of charge. The resulting data can be used by participants for publication, patenting and development purposes, and is fed back into the research community through an open-access database after a 2-year period during which information is kept confidential to the provider. CO-ADD is fundamentally asking two questions: can the community work together to address the global threat of antimicrobial resistance; and are there as yet undiscovered, novel antimicrobial compounds already present within our diverse global chemistry community?</p

De quelques catéchismes créoles anciens: oublis, pertes, disparitions, réapparitions, découvertes

Il existe, dans le très vaste domaine des études postcoloniales, des territoires contigus ou semblables qui connaissent des phénomènes communs mais aux histoires très différentes, sinon radicalement opposées : tels les catéchismes - en langues romanes - fruit de la colonisation. Plus précisément, à l’histoire des catéchismes issus de la colonisation hispano-américaine, s’oppose l’histoire des catéchismes issus de la colonisation française, de l’Amérique et d’ailleurs. Ces derniers arrivent un siècle et demi environ après les espagnols et se manifestent de tout autre manière ; différents en sont l’époque, la scène et les acteurs : les destinateurs mais surtout les destinataires. Ce travail se propose de retracer l’histoire souvent aventureuse des plus anciens catéchismes des colonies ou ex-colonies françaises de la Caraïbe et de l’Océan Indien ; écrits en créole ou, parfois, en d’autres langues autochtones, ils constituent aussi des témoignages linguistiques absolument précieux. Rédigés généralement sur place, mais non toujours publiés, leur histoire est faite d’oublis, pertes, disparitions, réapparitions et découvertes. - - - In the wide field of postcolonial studies, there exist related or similar areas whose stories are nevertheless very different, if not indeed opposed. This is the case of catechisms in Romance languages (or of Romance origin), outcomes of European colonization. In particular, contradictions between the history of catechisms from Hispanic-American colonization and the catechisms produced by French colonization, in America and elsewhere. The latter appear a century and a half after the Spanish texts, and exhibit completely distinct characteristics: different periods, settings, actors, and especially recipients. I set out to recount the often adventurous history of the oldest catechisms in the French colonies, or ex-colonies, of the Caribbean and the Indian Ocean. Written in Creole or sometimes other indigenous languages, they are precious linguistic records. Compiled in the colonies, but not always published, these texts are often forgotten, lost, misplaced, resurfaced, discovered

Carbohydrate scaffolds as glycosyltransferase inhibitors with in vivo antibacterial activity

The rapid rise of multi-drug-resistant bacteria is a global healthcare crisis, and new antibiotics are urgently required, especially those with modes of action that have low-resistance potential. One promising lead is the liposaccharide antibiotic moenomycin that inhibits bacterial glycosyltransferases, which are essential for peptidoglycan polymerization, while displaying a low rate of resistance. Unfortunately, the lipophilicity of moenomycin leads to unfavourable pharmacokinetic properties that render it unsuitable for systemic administration. In this study, we show that using moenomycin and other glycosyltransferase inhibitors as templates, we were able to synthesize compound libraries based on novel pyranose scaffold chemistry, with moenomycin-like activity, but with improved drug-like properties. The novel compounds exhibit in vitro inhibition comparable to moenomycin, with low toxicity and good efficacy in several in vivo models of infection. This approach based on non-planar carbohydrate scaffolds provides a new opportunity to develop new antibiotics with low propensity for resistance induction

Correction: Metal complexes as a promising source for new antibiotics

Correction for ‘Metal complexes as a promising source for new antibiotics’ by Angelo Frei et al., Chem. Sci., 2020, 11, 2627–2639

Elucidating the Lipid Binding Properties of Membrane-Active Peptides Using Cyclised Nanodiscs

The lipid composition of the cellular membrane plays an important role in a number of biological processes including the binding of membrane-active peptides. Characterization of membrane binding remains challenging, due to the technical limitations associated with the use of standard biophysical techniques and available membrane models. Here, we investigate the lipid binding properties of two membrane-active peptides, VSTx1, a well characterized ion-channel inhibitor, identified from spider venom, that preferentially binds to anionic lipid mixtures, and AA139 an antimicrobial β-hairpin peptide with uncharacterised lipid binding properties, currently in pre-clinical development. The lipid binding properties of these peptides are elucidated using nanodiscs formed by both linear and circularized (sortase-mediated) forms of a membrane scaffold protein (MSP1D1ΔH5). We find that nanodiscs formed by circularized MSPs—in contrast to those formed by linear MSPs—are sufficiently stable under sample conditions typically used for biophysical measurements (including lipid composition, a range of buffers, temperatures and concentrations). Using these circularized nanodiscs, we are able to extract detailed thermodynamic data using isothermal titration calorimetry (ITC) as well as atomic resolution mapping of the lipid binding interfaces of our isotope labeled peptides using solution-state, heteronuclear, nuclear magnetic resonance (NMR) spectroscopy. This represents a novel and general approach for elucidating the thermodynamics and molecular interface of membrane-active peptides toward flat lipid bilayers of variable composition. Our approach is validated by first determining the thermodynamic parameters and binding interface of VSTx1 toward the lipid bilayer, which shows good agreement with previous studies using lipid micelles and liposomes. The method is then applied to AA139, where the membrane binding properties are unknown. This characterization, involved solving the high-resolution structure of AA139 in solution using NMR spectroscopy and the development of a suitable expression system for isotope labeling. AA139 was found to bind exclusively to anionic membranes with moderate affinity (Kd~low μM), and was found to have a lipid binding interface involving the termini of the β-hairpin structure. The preference of AA139 for anionic lipids supports a role for membrane binding in the mode-of-action of this peptide, which is also consistent with its higher inhibitory activity against bacterial cells compared to mammalian cells. The described approach is a powerful method for investigation of the membrane binding properties of this important class of molecules

Synthesis of norbornane bisether antibiotics via silver-mediated alkylation

A small series of norbornane bisether diguanidines have been synthesized and evaluated as antibacterial agents. The key transformation-bisalkylation of norbornane diol 6-was not successful using Williamson methodology but has been accomplished using Ag2O mediated alkylation. Further functionalization to incorporate two guanidinium groups gave rise to a series of structurally rigid cationic amphiphiles; several of which (16d, 16g and 16h) exhibited antibiotic activity. For example, compound 16d was active against a broad range of bacteria including Pseudomonas aeruginosa (MIC = 8 &micro;g/mL), Escherichia coli (MIC = 8 &micro;g/mL) and methicillin-resistant Staphylococcus aureus (MIC = 8 &micro;g/mL)

Metal complexes as a promising source for new antibiotics

There is a dire need for new antimicrobial compounds to combat the growing threat of widespread antibiotic resistance. With a currently very scarce drug pipeline, consisting mostly of derivatives of known antibiotics, new classes of antibiotics are urgently required. Metal complexes are currently in clinical development for the treatment of cancer, malaria and neurodegenerative diseases. However, only little attention has been paid to their application as potential antimicrobial compounds. We report the evaluation of 906 metal-containing compounds that have been screened by the Community for Open Antimicrobial Drug Discovery (CO-ADD) for antimicrobial activity. Metal-bearing compounds display a significantly higher hit-rate (9.9%) when compared to the purely organic molecules (0.87%) in the CO-ADD database. Out of 906 compounds, 88 show activity against at least one of the tested strains, including fungi, while not displaying any cytotoxicity against mammalian cell lines or haemolytic properties. Herein, we highlight the structures of the 30 compounds with activity against Gram-positive and/or Gram-negative bacteria containing Mn, Co, Zn, Ru, Ag, Eu, Ir and Pt, with activities down to the nanomolar range against methicillin resistant S. aureus (MRSA). 23 of these complexes have not been reported for their antimicrobial properties before. This work reveals the vast diversity that metal-containing compounds can bring to antimicrobial research. It is important to raise awareness of these types of compounds for the design of truly novel antibiotics with potential for combatting antimicrobial resistance