Targeting antibiotic resistance

Finding strategies against the development of antibiotic resistance is a major global challenge for the life sciences community and for public health. The past decades have seen a dramatic worldwide increase in human-pathogenic bacteria that are resistant to one or multiple antibiotics. More and more infections caused by resistant microorganisms fail to respond to conventional treatment, and in some cases, even lastresort antibiotics have lost their power. In addition, industry pipelines for the development of novel antibiotics have run dry over the past decades. A recent world health day by the World Health Organization titled “Combat drug resistance: no action today means no cure tomorrow” triggered an increase in research activity, and several promising strategies have been developed to restore treatment options against infections by resistant bacterial pathogens

Antibiotikaresistenzen gezielt überwinden

Neue Strategien zur Bekämpfung von Antibiotikaresistenzen zu finden, ist eine der grössten globalen Herausforderungen für die Gesundheitssysteme. In den letzten Jahrzehnten gab es eine drastische Zunahme an humanpathogenen Bakterien, die resistent gegen Antibiotika sind. Immer mehr Infektionen, die durch resistente Mikroorganismen verursacht werden, lassen sich nicht mehr mit konventionellen Behandlungen kurieren, und selbst Reserveantibiotika verlieren ihre Wirkung. Zusätzlich sind die Entwicklungsströme an neuen Antibiotika aus der pharmazeutischen Industrie in den letzten Jahrzehnten versiegt. Die Weltgesundheitsorganisation hat mit ihrem Aufruf „Combat drug resistance: no action today means no cure tomorrow“ eine Zunahme der Forschungsaktivitäten auf diesem Gebiet stimuliert, und mehrere neue,vielversprechende Strategien zur Wiederherstellung antibiotischer Behandlungsoptionen konnten seitdem entwickelt werden

Biocompatibilité, biodégradation et influence de la stérilisation sur le complexe chitosane-xanthane

Chitine/chitosane -- Le xanthane -- Complexes polymériques -- Étude de la biocompatibilité -- Étude de la biodégradation -- Étude des effets de la stérilisation sur les propriétés physico-chimiques des films de chitosane-xanthane -- Résultats des études de la biocompatibilité in vitro et in vivo -- Résultat des études de la biodégradation -- Résultats de l'étude de la stérilisation (non publiés)

METHYLENETETRAHYDROFOLATE REDUCTASE C677T GENE POLYMORPHISM AND PROSTATE CANCER RISK

Objective: The single nucleotide polymorphism C677T of the methylenetetrahydrofolate reductase (MTHFR) gene encodes a thermolabile enzyme. This polymorphism was found to be implicated in cancer susceptibility. In this study, we analyzed the distribution of the MTHFR C677T polymorphism in two cohorts; patients and controls native of East of Algeria to explore the possible association between this polymorphism and prostate cancer susceptibility.Methods: Our examination has been conducted in 98 cases and 98 healthy controls. Genotyping was realized by polymerase chain reaction-restriction fragment length polymorphism method.Results: Compared with CC homozygous, the CT heterozygous was found to have a significantly increased risk of prostate cancer (p=0.04; odds ratio [OR]=2.01, 95% confidence interval [CI]: 1.02–3.95). However, no statistically significant difference was observed concerning the TT homozygous (p=0.74; OR=1.25, 95% CI: 0.51–3.04).Conclusion: Our results indicate that the genotype CT is a risk factor for prostate cancer in East of Algeria

Association of single nucleotide polymorphisms with renal cell carcinoma in Algerian population

Background: Renal cell carcinoma (RCC) is a common malignant tumor of the urinary system. The etiology of RCC is a complex interaction between environmental and multigenetic factors. Genome-wide association studies have iden? tifed new susceptibility risk loci for RCC. We examined associations of genetic variants of genes that are involved in metabolism, DNA repair and oncogenes with renal cancer risk. A total of 14 single nucleotide polymorphisms (SNPs) in 11 genes (VEGF, VHL, ATM, FAF1, LRRIQ4, RHOBTB2, OBFC1, DPF3, ALDH9A1 and EPAS1) were examined. Methods: The current case?control study included 87 RCC patients and 114 controls matched for age, gender and ethnic origin. The 14 tag-SNPs were genotyped by Sequenom MassARRAY? iPLEX using blood genomic DNA. Results: Genotype CG and allele G of ATM rs1800057 were signifcantly associated with RCC susceptibility (p=0.043; OR=8.47; CI=1.00?71.76). Meanwhile, we found that genotype AA of rs67311347 polymorphism could increase the risk of RCC (p=0.03; OR=2.95; IC=1.10?7.89). While, genotype TT and T allele of ALDH9A1 rs3845536 were observed to approach signifcance for a protective role against RCC (p=0.007; OR=0.26; CI=0.09?0.70). Conclusion: Our results indicate that ATM rs1800057 may have an efect on the risk of RCC, and suggest that ALDH9A1 was a protective factor against RCC in Algerian populatio

Electrochemical preparation of chitosan/hydroxyapatite composite coatings on titanium substrates

Composite coatings containing brushite (CaHPO4 • 2H2O) and chitosan were prepared by electrochemical deposition. The brushite/chitosan composites were converted to hydroxyapatite/chitosan composites in aqueous solutions of sodium hydroxide. The coatings ranged from 1 to 15% chitosan by weight. Qualitative assessment of the coatings showed adhesion signifi cantly improved over that observed for electrodeposited coatings of pure HA

Development of osteoblast colonies on new bioactive coatings

The aging baby boomer population coupled with an increase in life expectancy is leading to a rising number of active elderly persons in occidental countries. As a result, the orthopedic implant industry is facing numerous challenges such as the need to extend implant life, reduce the incidence of revision surgery, and improve implant performance. This paper reports results of an investigation on the bioperformance of newly developed coating-substrate systems. Hydroxyapatite (HA) and nano-titania (nano-TiO\u2082) coatings were produced on Ti-6Al-4V and fiber reinforced polymer composite substrates. In vitro studies were conducted to determine the capacity of bioactive coatings developed to sustain osteoblast cells (fetal rat calvaria) adherence, growth, and differentiation. As revealed by scanning electron microscopy (SEM) observations and alkaline phosphatase activity, cell adhesion and proliferation demonstrated that HA coatings over a polymer composite are at least as good as HAcoatings made over Ti-6Al-4V substrate in terms of osteoblast cell activity. Nano-TiO\u2082 coatings produced by high-velocity oxyfuel (HVOF) spraying led to different results. For short-term cell culture (4.5 and 24 h), the osteoblasts appeared more flattened when grown on nano-TiO\u2082 than on HA. The surface cell coverage after seven days of incubation was also more complete on nano-TiO\u2082 than HA. Preliminary results indicate that osteoblast activity after 15 days of incubation on nano-TiO\u2082 is equivalent to or greater than that observed on HA.Peer reviewed: YesNRC publication: Ye

Entrapment ability and release profile of corticosteroids from starch-based microparticles

We previously described the synthesis of starchbased microparticles that were shown to be bioactive (when combined with Bioactive Glass 45S5) and noncytotoxic. To further assess their potential for biomedical applications such as controlled release, three corticosteroids with a similar basic structure—dexamethasone (DEX), 16-methylprednisonole (MP), and 16-methylprednisolone acetate (MPA) - were used as models for the entrapment and release of bioactive agents. DEX, MP, and MPA were entrapped into starch-based microparticles at 10% wt/wt of the starch-based polymer and the loading efficiencies, as well as the release profiles, were evaluated. Differences were found for the loading efficiencies of the three corticosteroids, with DEX and MPA being the most successfully loaded (82 and 84%, respectively), followed by MP (51%). These differences might be explained based on the differential distribution of the molecules within the matrix of the microparticles. Furthermore, a differential burst release was observed in the first 24 h for all corticosteroids with DEX and MP being more pronounced (around 25%), whereas only 12% of MPA was released during the same time period. Whereas the water uptake profile can account for this first stage burst release, the subsequent slower release stage was mainly attributed to degradation of the microparticle network. Differences in the release profiles can be explained based on the structure of the molecule, because MPA, a more bulky and hydrophobic molecule, is released at a slower rate compared with DEX and MP. In this work, it is shown that these carriers were able to sustain a controlled release of the entrapped corticosteroids over 30 days, which confirms the potential of these systems to be used as carriers for the delivery of bioactive agents

Reducing the Flexibility of Type II Dehydroquinase for Inhibition: A Fragment‐Based Approach and Molecular Dynamics Study

This is the peer-reviewed version of the following article: Peón, A., Robles, A., Blanco, B., Convertino, M., Thompson, P., & Hawkins, A. et al. (2017). Reducing the Flexibility of Type II Dehydroquinase for Inhibition: A Fragment-Based Approach and Molecular Dynamics Study. Chemmedchem, 12(18), 1512-1524, which has been published in final form at https://doi.org/10.1002/cmdc.201700396. This article may be used for non-commercial purposes in accordance with Wiley-VCH Terms and Conditions for Self-ArchivingA multidisciplinary approach was used to identify and optimize a quinazolinedione‐based ligand that would decrease the flexibility of the substrate‐covering loop (catalytic loop) of the type II dehydroquinase from Helicobacter pylori. This enzyme, which is essential for the survival of this bacterium, is involved in the biosynthesis of aromatic amino acids. A computer‐aided fragment‐based protocol (ALTA) was first used to identify the aromatic fragments able to block the interface pocket that separates two neighboring enzyme subunits and is located at the active site entrance. Chemical modification of its non‐aromatic moiety through an olefin cross‐metathesis and Seebach's self‐reproduction of chirality synthetic principle allowed the development of a quinazolinedione derivative that disables the catalytic loop plasticity, which is essential for the enzyme′s catalytic cycle. Molecular dynamics simulations revealed that the ligand would force the catalytic loop into an inappropriate arrangement for catalysis by strong interactions with the catalytic tyrosine and by expelling the essential arginine out of the active siteSecretaría de Estado de Investigación, Desarrollo e Innovación. Grant Numbers: SAF2013-42899-R, SAF2016-75638-R Consellería de Cultura, Educación e Ordenación Universitaria, Xunta de Galicia. Grant Number: ED431G/09 European Regional Development Fund Ministerio de Educación, Cultura y DeporteS

Carnauba wax nanoparticles enhance strong systemic and mucosal cellular and humoral immune responses to HIV-gp140 antigen

Induction of humoral responses to HIV at mucosal compartments without inflammation is important for vaccine design. We developed charged wax nanoparticles that efficiently adsorb protein antigens and are internalized by DC in the absence of inflammation. HIV-gp140-adsorbed nanoparticles induced stronger in vitro T-cell proliferation responses than antigen alone. Such responses were greatly enhanced when antigen was co-adsorbed with TLR ligands. Immunogenicity studies in mice showed that intradermal vaccination with HIV-gp140 antigen-adsorbed nanoparticles induced high levels of specific IgG. Importantly, intranasal immunization with HIV-gp140-adsorbed nanoparticles greatly enhanced serum and vaginal IgG and IgA responses. Our results show that HIV-gp140-carrying wax nanoparticles can induce strong cellular/humoral immune responses without inflammation and may be of potential use as effective mucosal adjuvants for HIV vaccine candidates