Periodic Reporting for period 2 - ALERT (Local Training Network on Novel Tailor-Made Antimicrobials and Delivery Strategies From Synthesis towards Clinical Applications)
Okres sprawozdawczy: 2018-05-01 do 2021-04-30
The development of antibiotics almost completely extinguished infectious diseases, such as tuberculosis, pneumonia, typhoid fever and meningitis in the 19th and 20th centuries. In the 21st century, however, the overuse of antibiotics led to the emergence of multidrug resistant (MDR) bacteria. Therefore, besides classical antibiotic development, alternative strategies employing modern tools from nanotechnology or synthetic biology need to be pursued.
The local training network ALERT addresses this challenge by establishing a dedicated doctoral training program with an international, interdisciplinary and inter-sectoral focus. Nineteen excellent Early Stage Researchers (ERSs) conducted cutting-edge research projects in the field of antimicrobials and have been trained in specialist advanced courses, training schools and other networking activities.
ALERT has contributed to the major goal to overcome the thread of MDR bacteria through the development of novel antimicrobial drug candidates by chemical, biotechnological and nanotechnological synthesis and the subsequent testing of promising candidates in vivo. The objectives have been distributed into four tasks. Task 1 was focused on methods to shorten the time for identifying and preparing novel antimicrobial molecules using innovative chemical synthesis approaches. Task 2 was dedicated to the development of new antimicrobials at a biotechnological level, exploiting rational design and synthetic biology construction principles. In addition, task 3 addressed nanotechnology approaches to create new antimicrobials that can locally fight pathogens. Task 4 covered the in vivo testing of promising antimicrobial drug candidates resulting from Tasks 1-3.
The local training network ALERT addresses this challenge by establishing a dedicated doctoral training program with an international, interdisciplinary and inter-sectoral focus. Nineteen excellent Early Stage Researchers (ERSs) conducted cutting-edge research projects in the field of antimicrobials and have been trained in specialist advanced courses, training schools and other networking activities.
ALERT has contributed to the major goal to overcome the thread of MDR bacteria through the development of novel antimicrobial drug candidates by chemical, biotechnological and nanotechnological synthesis and the subsequent testing of promising candidates in vivo. The objectives have been distributed into four tasks. Task 1 was focused on methods to shorten the time for identifying and preparing novel antimicrobial molecules using innovative chemical synthesis approaches. Task 2 was dedicated to the development of new antimicrobials at a biotechnological level, exploiting rational design and synthetic biology construction principles. In addition, task 3 addressed nanotechnology approaches to create new antimicrobials that can locally fight pathogens. Task 4 covered the in vivo testing of promising antimicrobial drug candidates resulting from Tasks 1-3.
Within the project ALERT we were able to identify several new candidates of antibiotic molecules. Derived from aminoglycosides we have found multiple candidates that could become novel antibiotic lead compounds. We have reported about a new class of selective, antibacterial agents inhibiting the energy-coupling factor (ECF) transporters with an unprecedented mode of action. In addition, we reported novel modified lantibiotic variants, which represent a highly active class of peptide antibiotics. Moreover, we have expanded the approach to selectively activate antimicrobial drugs by light (photopharmaceuticals) and developed a unique approach to activate antimicrobial drugs by ultrasound, which we coined sonopharmaceuticals.
New molecular targets have been determined and have been used to apply rational design principles based on molecular modelling and in depth characterisation of the identified structures within the pathogens. Quorum sensing (QS) as a pivotal step in the formation of biofilms has been addressed by the rational design and utilization of quorum quenching enzymes and surface modifications that interfere with QS. These are novel approaches on how to control and manage biofilm derived chronic infections. In addition, we contributed to the development of new probes and models to elucidate molecular mechanism of antimicrobial drugs as well as mechanisms of pathogens to escape antimicrobials and the immune system.
The ESRs have published their results in 41 scientific papers, including high impact journals, such as Nature Communications and Nature Chemistry. Another 3 papers have been accepted, while 8 other papers are still under review. The ESRs further disseminated their results in scientific congresses and symposia, both within the Netherlands and abroad. They participated in 51 (international) conferences, such as CHAINS and the EMBO/EMBL Symposium: New Approaches and Concepts in Microbiology. ESRs participated 14 times as a speaker and 37 times with a poster.
New molecular targets have been determined and have been used to apply rational design principles based on molecular modelling and in depth characterisation of the identified structures within the pathogens. Quorum sensing (QS) as a pivotal step in the formation of biofilms has been addressed by the rational design and utilization of quorum quenching enzymes and surface modifications that interfere with QS. These are novel approaches on how to control and manage biofilm derived chronic infections. In addition, we contributed to the development of new probes and models to elucidate molecular mechanism of antimicrobial drugs as well as mechanisms of pathogens to escape antimicrobials and the immune system.
The ESRs have published their results in 41 scientific papers, including high impact journals, such as Nature Communications and Nature Chemistry. Another 3 papers have been accepted, while 8 other papers are still under review. The ESRs further disseminated their results in scientific congresses and symposia, both within the Netherlands and abroad. They participated in 51 (international) conferences, such as CHAINS and the EMBO/EMBL Symposium: New Approaches and Concepts in Microbiology. ESRs participated 14 times as a speaker and 37 times with a poster.
Presently, companies are afraid of investment in early discovery, but once the risk has been taken by others (academic groups in this case), pharmaceutical or biotech industry might step forward to enter clinical application. While clinical trials have been beyond the scope of this project, our discoveries and training has shown new ways to antimicrobials and made the next step possible, which might save lives in the future.
Within the research program of ALERT several synthetic methods, chemical and biotechnological, were developed and refined that can avoid cumbersome and tedious multistep synthesis and reduce the time effort necessary. Supported by rational design principles and by in-depth analysis of pathogen transporter proteins, we have developed new antimicrobials and antibacterial agents. We demonstrated the huge benefit of top-notch selective and interactive approaches involving photopharmacology, sonopharmacology and nanotechnology.
Within the research program of ALERT several synthetic methods, chemical and biotechnological, were developed and refined that can avoid cumbersome and tedious multistep synthesis and reduce the time effort necessary. Supported by rational design principles and by in-depth analysis of pathogen transporter proteins, we have developed new antimicrobials and antibacterial agents. We demonstrated the huge benefit of top-notch selective and interactive approaches involving photopharmacology, sonopharmacology and nanotechnology.