H2020Индивидуална стипендия2015–2017

COMMANDEER · Disrupting microbial resistance using rationally designed signalling molecules

„Хоризонт 2020“ — Действия „Мария Склодовска-Кюри“

Период: 2015-07-01 → 2017-06-30
Финансиране от ЕС: 187 866 €
Участници: 1
Схема: MSCA-IF-EF-ST

Линиите свързват координатора с партньорите.

Накратко на български

Молекули, които прекъсват комуникацията между бактерии като P. aeruginosa, се тестват за повишаване ефекта на антибиотиците. Това е важно, защото помага при лечението на белодробни инфекции при пациенти с кистична фиброза, при които стандартните лекарства често стават неефективни.

Този кратък обзор е генериран от изкуствен интелект

Кратко обяснение, генерирано от езиков модел по текста на CORDIS. Оригиналът е по-долу.

Резултати накратко

COMMANDEER: Disrupting microbial resistance using rationally designed signalling molecules

Lung disease is the leading cause of morbidity and mortality in cystic fibrosis (CF) patients. Over time, there has arisen an increasing appreciation for the polymicrobial nature of such infections and the potentially important role for interspecies interactions in influencing both bacterial virulence and response to therapy. Chronic colonisation and infection by P. aeruginosa occurs in 80% of CF patients by 18 years of age, and patients are commonly co-infected by other pathogens such as B. cenocepacia and S. maltophilia. B. cenocepacia has emerged as an important pathogen frequently associated with high mortality in CF patients. This pathogen produces signal molecules of the DSF family, which are simple fatty acids. Molecules that target cell-to-cell signalling (Quorum Sensing/QS) have been proposed as a strategy that could be added to the existing arsenal in treating bacterial infections. Traditionally, antibiotics have been used to combat bacterial infections. Although these compounds were initially highly effective, they resulted in substantial stress on the target bacterium, which rapidly selected for multi-antibiotic resistant bacteria. Additionally, the number of new effective antibiotics brought to market is steadily falling. The overall aim of COMMANDEER was to build upon a very promising pilot study demonstrating that DSF analogue compounds interfere with cell-to-cell signalling processes in P. aeruginosa making them significantly more susceptible to antibiotic treatment. We have identified antagonists which can be co-administered with current antibiotics forming the basis of future therapies for CF. We carried out a deeper investigation of the relationship between structure and activity, ability to permeate biofilms and spectrum of activity of these analogues. A collaborative and multidisciplinary approach was used, incorporating chemical and biomolecular techniques, to generate a library of bioisosteric analogues of DSF, evaluate their ability to interfere with DSF cell-to-cell signalling processes in bacteria that colonize the CF lung and select those compounds which improve the efficacy of antibiotic treatment of bacterial infections.

Текст от CORDIS, на английски · Данни: CORDIS, © Европейски съюз

Цел на проекта

Cystic Fibrosis (CF) is an inherited disease which affects 100,000 people worldwide and is prevalent in European populations. CF causes the body to produce an abnormally sticky mucus in the lungs making patients susceptible to serious bacterial infection. By age 8, 50% of CF patients are infected with Pseudomonas aeruginosa increasing to 80% by 20 years of age. Eventually, the infecting strains of bacteria become resistant to antibiotics and remain a chronic inhabitant of the lungs of CF patients until they succumb to respiratory failure, usually by the young age of 30-35. Approximately 60% of CF patients are co-infected with Burkholderia cenocepacia that settle into the thick mucus of the airways. These bacteria have evolved a special type of defence mechanism to antibiotics whereby they excrete a chemical messenger on treatment. This chemical messenger -Diffusible Signal Factor or DSF - activates bacterial biofilm formation. Previous work has shown that DSF effectively behaves as an ‘emergency flare’ to other bacteria, which produce a biofilm in response. This biofilm acts as a shield which protects the bacteria from the effects of antibiotics.As a key fits in a lock, DSF fits into bacterial receptors and “switches on” biofilm formation. In this COMMANDEER project, we will synthesise molecules which mimic DSF and fit into the same biological receptors. However, due to subtle changes in their design, our molecules will “switch off” biofilm formation. Using this novel strategy of effectively commandeering the bacteria’s signalling system, we will disable biofilm formation, making the bacteria susceptible to antibiotics once again. We will adopt a multidisciplinary and collaborative approach combining the talents of chemists in Ireland and microbiologists in the UK. This project, therefore, represents a new and exciting route of circumventing bacterial resistance, offering significantly improved quality of life for CF patients and increased life expectancies.

Оригинален текст от CORDIS (на английски).

Участници

UNIVERSITY COLLEGE CORK - NATIONAL UNIVERSITY OF IRELAND, CORK · CorkКоординаторИрландия