Mercoledì del PRIN n.1: Francesca Petronella – Flora Tommasello

Investigation on the nanoparticles-driven controlled delivery of antimicrobial peptides to treat dermatological infections

Dr. Francesca Petronella

The project aims at developing targeted therapeutic approaches to treat acne, and potentially other chronic relapsing cutaneous diseases which are influenced by dysbiosis. The project will realize smart medical devices (SMD), namely gauzes and patches, pre-loaded with antimicrobial peptides (AMP). The SMD will be made of biocompatible polymers functionalized with photoactive nanomaterials. The thermoplasmonic heating will promote the controlled release of AMPs. The SMD will be tested on patients recruited in accord to the ethical procedures. The biochemistry and microbiology expertise from the PI will complete the framework by choosing and testing the most interesting AMPs and analysing the effect of the treatments on the follicular microbiome. Our strategy, inspired by the innate immunity mechanisms foresees the benefit of applying the topic treatment only on a localised area and for a limited duration, thereby avoiding the exposure of the patient to antibiotics and the risk to develop multidrug resistant (MDR) bacteria. The choice of acne is due to its high incidence especially in adolescent population (about 90%) often compromising the patient’s quality of life, and negatively affecting their compliance to the treatment. Current treatment algorithms for acne include the use of antibiotics for 8-12 weeks which further expose this young population group to the risk of developing antimicrobial resistance (AMR) if they do not adhere to prescriptions. The AMR is a global threat, and MDR bacteria spread easily, posing a therapeutic problem in all fields of medicine. In this respect one of the microorganisms pathogenically associated to acne as well as atopic dermatitis is the Staphylococcus aureus that belongs to the ESKAPE group, a major global concern as carriers of MDR. Avoiding the mis/over-use of antibiotics, while exploring alternative (or adjuvant) paths, is an urgent need and fully within the UN SDG3 (Good Health and Well-Being).

Ambiti:

Salute, Materiali

Keywords:

1. combating antimicrobial resistance;
2. nanocomposite;
3. thermoplasmonics;
4. electrospinning;
5. acne;
6. dysbiosis

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Deciphering the molecular basis of VDAC-Hexokinase interaction

Dr. Flora Tommasello

Hexokinase (HK) initiates the glycolytic pathway by sequestering glucose as 6Pi-glucose within the cell. To access ATP for phosphorylation conveniently, HK binds to mitochondria surfaces using Voltage Dependent Anion Selective Channel (VDAC). This HK-VDAC binding influences the apoptotic balance and is considered a hallmark of cancer cells known as the Warburg effect. The binding mechanism between HK and VDAC remains elusive. HK, a soluble enzyme, requires its short N-terminal hydrophobic tail for organelle binding, while VDAC E73 deletion disrupts this interaction. A recent MD simulation challenges this, proposing a new HK-VDAC1 binding model.

This project aims to pinpoint residues facilitating VDAC1 and HKI binding. Two strategies will be employed: i) producing VDAC1 mutants with cysteine residues in potential binding regions and introducing cysteines in synthetic peptides with N-HK sequences, promoting oxidation and disulfide formation; ii) using the entire HKI, inducing binding via chemical cross-linking reagents or click chemistry. Bioinformatic analyses will utilize docking tools to examine interactions between the hydrophobic N-HK sequence and the pore wall, as well as hydrophilic surfaces of HK and cytosolic loops of VDAC. Validation involves introducing modified proteins into cells and analyzing their impact on vitality and mitochondrial polarization.

Ambiti:

Life Science

Keywords:

1. Mitochondria,
2. Protein-protein interaction,
3. Metabolic regulation,
4. Warburg effect