ACFs PROJECT

Project

ACFs: Antibiotic Coordination Frameworks
as a way to enhance the bioactivity of the drugs
PTDC/QUI-OUT/30988/2017
LISBOA-01-0145-FEDER-030988

AIMS AND BACKGROUND OF THE PROJECT
The goal of this project is to develop new metal-organic frameworks (MOFs) of antibiotics to increase their solubility, and consequently bioavailability, trying also to explore synergetic effects with the metal, such as zinc, silver and bismuth, to increase the antibiotic’s efficacy. Actually, both factors lead to enhanced efficacy. MOFs proposed herein are also a viable way for a more controlled delivery and release of antibiotics.
Another important point of this project is that mechanochemistry is the main synthetic pathway proposed in this project. This is an environment-friendly technique that drastically reduces the amount of solvents and it has proven to be very efficient in different areas including MOFs’ synthesis.
The interest on metal-organic frameworks towards pharmacological applications has been increasing, especially for controlled drug delivery and release. However, the coordination of metals can also be an alternative way to induce significant changes in previously known drugs, changing important properties such as solubility and bioavailability, with the further advantage that synergetic effects of the metal can be explored enhancing its performance.
Bactericidal agents, including antibiotics, drastically reduced the number of deaths caused by infections over the last 70 years. However, due to their misuse and abuse, many microorganisms developed resistance mechanisms, causing only in Europe approximately 25000 deaths/year, an economic burden over 1.5 bilion € and productivity losses. Thus, there is a growing concern about the proliferation of these multi-resistant Gram-negative microorganisms against which the antibiotics have become less effective and it is indeed one of the great challenges of today’s society.

KEYWORDS
Mechanochemistry; Powder X-Ray Diffraction; Single Crystal X-Ray Diffraction; Antibiotic Coordination Frameworks; Safe Metals; Bioactivity; Multiresistant microorganisms

FIELDS OF EXPERTISE

Mechanochemistry

Mechanochemistry is a versatile environment-friendly synthetic technique with a very wide scope of applications, which has proved to promote, promptly and quantitatively, reactions between solids, with either no added solvent or only using catalytic amounts of solvents.

Structural characterization

The team has a strong background in using X-ray diffraction data and crystallography for structural characterization.
The topological analysis follows the structure determination, enabling classification, identification, and prediction of different topological motifs.
To establish structure-property relationships is of great importance and can be useful in the design of future systems.
Molecular dynamics and theoretical calculations may bring further insights to this analysis.

New drug forms towards improved properties

Antimicrobial activity

Crystalline APIs can exist in a variety of forms, including polymorphs, solvates, hydrates, salts, and co-crystals. Each of these forms displays unique physicochemical properties that can deeply influence solubility, dissolution profile, bioavailability, manufacturability, temperature and humidity stabilities, hygroscopicity as well as other performance characteristics of the drug.
However, also metal complexes and metal-organic frameworks can be used to trigger properties' modifications. In this project we are particularly interested in the solubility (closely related to bioavailability) and in the antimicrobial activity of the novel ACFs.

Antimicrobial resistance to multiple drugs is an important issue in public health and a huge challenge to scientists nowadays. Different strategies have been used to improve the antimicrobial activity of numerous compounds.
One way to overcome this multiresistance problem is the coordination of biocompatible metals to antibiotics. This strategy has been shown to be a valid way to obtain alternative compounds with improved antimicrobial activity.
Antimicrobial agents can kill or inhibit the development of the disease's causing microbes, like bacteria, fungi and/or viruses.
The determination of the antimicrobial activity of the novel compounds is the indicator of the success of the strategy employed herein.

FUNDING

“Redes de coordenação de antibióticos como forma de potenciar a bioactividade dos fármacos – ACFs” é financiado pelo Fundo Europeu de Desenvolvimento Regional (FEDER) através do Programa Operacional Regional de Lisboa e por Fundos Nacionais através da FCT - Fundação para a Ciência e a Tecnologia (LISBOA-01-0145-FEDER-030988 / PTDC/QUIOUT/30988/2017)