Projects In-Course

1 .- Development of Silver-Silica nanocarriers and their stabilisation in solid materials against pathogen bacteria. Towards advanced nano-antibiotics, wound dressing and anti-biofilm surfaces.   SiSi4Bacter

PDTC/COL-QUI/1515/2020 FCT MEC

Funding: 233.032,55 Euros

PI: Dr. Javier Fernandez Lodeiro

CoPI: Dr. Carlos Lodeiro Espiño

Abstract

Bacteria induced-infectious are a worldwide problem and responsible for numerous cases of morbidity and mortality.1 For instance, wound infections in diabetic patients, increasingly lead to amputations; as a consequence of bacterial infections that do not respond to the administration of conventional drugs.2 The over-use of antibiotics has resulted in the spread of resistant bacteria. In consequence, there is an urgent need to develop new antimicrobial agents towards pathogenic bacteria. In such a situation, silver-based materials, that that were already widely used by ancient civilizations, has resurfaced as a potent therapeutic option, as evidenced by the increasing number of publications and patents related to the application of silver materials.3,4

Actually, the manipulation of this metal at the nano-metric scale to engineer nanoparticleshas reinforced its therapeutic effectscompared with their silver-bulk conunterpart.5 In recent decades, the fine control in silver colloidal chemistry has allowed the synthesis of AgNPs in wide range of shapes and sizes.6 Note that AgNPs show different susceptibility to oxidation (therefore differentiated anti-microbial effect) depending on their size and shape.7

Additionally to the ionic silver release effect, surface charge,8,9 and/or molecular functionalization (e.g. antibiotics drugs)10 have been shown improve the antimicrobial effects of Agor even AuNPs.8 As an example between many others, our group has discovered a synthetic route to produce silver NPs in sizes of 15 or 25 nm using tetracycline as a reducing and stabilizing agent. The as so synthesized NPs showed potent antibacterial effects against Gram+ and Gram- pathogenic bacteria. More importantly, a potent antimicrobial effect against tetracycline-resistant bacteria was also observed.11

Unfortunately, there is still a long way to properly implement this “Holy Grail” biocide. Common drawbacks that silver AgNPs or their organically functionalized analogues present are related to their colloidal stability in biological medium. The aggregation process that, usually, AgNPs undergo/suffer can hinder their antimicrobial effect.12 On the other hand, the high oxidation tendency can hinders their consistent application as a bacterial agent during long time periods.13 Therefore, while the benefits of AgNPs are attracting increasing attention, several publications have pointed out potential adverse effects from the overuse of silver, such as ecosystem disturbance,14 health effects15 or even bacterial resistance to silver.12 At this stage, silver NPs represent a new hope, but conscious use should be considered since early stage to avoid the repetition of past mistakes. To overcome this situation, a coating where Ag NPs are immobilized and containable, can permit the control of ionic silver release in solution, the subsequent organic functionalization and also with a biocompatible character, can become a powerful strategy that will allow the implementation of AgNPs as a safe antibacterial agent in a multitude of applications.

With these considerations in mind, we propose the synthesis of a novel library of nanocarriers based on silver and silica (Ag@Si, Ag@Si@Simes and Ag@GAP@Simes) for the application in bacteriological control. The design proposed here would be flexible and convenient to control the bacterial adhesion properties, as well as load and release behaviour of drug and silver ionic species. The nanocarriers will be conjugated with commercial antimicrobial drugs (Amikacin, Kantamycin Oxacillin and Doxorubicin) in order to study cytotoxicity, bacterial adhesion properties, drug/ionic silver release as well as analysis of the antimicrobial properties against pathogenic Gram+ and Gram- bacteria. Furthermore, stabilization of nanocarriers in PVA hydrogels and surface deposition via electrospray technics are proposed to obtain advanced antimicrobial wound dressing and surfaces. 

 

2  .- Unlocking the secrets of sumoylation and phosphorylation crosstalk in neurodegeneration using new sumo/phospho-nano traps and quantitative proteomics.

PI: Dr. Hugo M. Santos

Fungind: 50,000.00 Euros

 Parkinson, Alzheimer, and brain cancer are characterized by malfunction of cellular signalling networks as a consequence of deregulation of a delicate mechanism of crosstalk between protein phosphorylation and sumoylation. Understanding how phosphorylation and sumoylation impacts cellular signalling networks and its role in disease, has eluded the research community to date because they are dynamic, both occurring at low abundance and both are linked to each other in a complex equilibrium where phosphorylation can either enhance or inhibit sumoylation leading to conformational changes of the substrate protein, altering its activity and function. Herein, a three-dimensional (3D) approach is proposed to overcome these challenges. This 3D method encompasses capturing sumoylated-proteins and phosphorylated peptides at a given time, in a given space and under a given equilibrium using new sumo/phospho-nano traps and quantitative proteomics. We propose to apply this workflow to study the role of sumoylation and phosphorylation crosstalk in brain neurodegeneration and cancer in mice as a consequence exposure to ultrafine particulate matter present in air pollution. The identification of specific alterations of phosphorylation and sumoylation crosstalk and its functional impact will cast light in the mechanisms of neurodegeneration and cancer that can be particularly interesting to select potential targets for new drugs to slow the development and progression of neurodegeneration.

 

 

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