Descripción del proyecto
Un método innovador para superar la resistencia a los antimicrobianos en bacterias gramnegativas
La resistencia a los antimicrobianos, asociada a patógenos multirresistentes, constituye una emergencia sanitaria mundial. Las bacterias gramnegativas impiden un tratamiento eficaz al impermeabilizar su membrana externa (ME) frente a los antibióticos de referencia. La red de investigación y formación del proyecto BREAKthrough, financiado por las Acciones Marie Skłodowska-Curie, se propone sensibilizar estas bacterias a los antibióticos de referencia al hacer permeable su ME. Parar ello, se desarrollarán inhibidores de tres mecanismos proteicos responsables del mantenimiento de la permeabilidad de la ME. Los objetivos son: desarrollar nuevas reglas químicas espaciales para fármacos que atraviesan la ME; descubrir inhibidores de mantenimiento de la ME para superar la resistencia a los antibióticos de referencia; y formar a once doctorandos para convertirse en desarrolladores profesionales de fármacos industriales.
Objetivo
Antimicrobial resistance, which is caused by multi-drug-resistant bacterial pathogens is a global health emergency. Gram-negative bacteria (GNB) notably hinder effective treatment because of their impermeable outer membrane (OM). Consequently, many standard-of-care (SOC) antibiotics cannot access intracellular targets in GNB.
The objective of the BREAKthrough European Training Network (ETN) is to sensitise GNB to these antibiotics by making their OM permeable. To this end, we will develop inhibitors of three protein machineries that are responsible for OM maintenance. Importantly, many known antibacterial agents have characteristics different from drugs that are directed against targets in mammalian cells. To define better rules for antibacterial drug development a data hub will be created to assemble information on the physico-chemical characteristics of molecules that can pass the OM.
To achieve these goals, a multi-disciplinary academic-industrial consortium has been assembled with organic chemists, computational chemists and specialists in high-throughput drug screening, zebrafish infection models, bacterial morphogenesis and the molecular biology of the three targets. The expected outcomes of the BREAKthrough ETN include (i) the development of new chemical space rules for drugs that need to cross the OM, (ii) the discovery of new inhibitors that interfere with OM maintenance to overcome the insensitivity of Gram-negative pathogenic bacteria towards SOC antibiotics and (iii) providing 10 Early Stage Researchers with scientific, technical, business and transferable skills to become professional drug developers with a keen eye for the hurdles in the development of these drugs in an industrial context.
Ámbito científico
- medical and health sciencesbasic medicinepharmacology and pharmacydrug discovery
- natural sciencesbiological sciencesmicrobiologybacteriology
- medical and health sciencesbasic medicinepharmacology and pharmacypharmaceutical drugsantibiotics
- medical and health sciencesbasic medicinepharmacology and pharmacydrug resistanceantibiotic resistance
- natural sciencesbiological sciencesmolecular biology
Palabras clave
Programa(s)
- HORIZON.1.2 - Marie Skłodowska-Curie Actions (MSCA) Main Programme
Régimen de financiación
HORIZON-TMA-MSCA-DN - HORIZON TMA MSCA Doctoral NetworksCoordinador
1348 Louvain La Neuve
Bélgica