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An integrated mulTidisciplinary appRoach towards a new generAtIon of aNtibiotics: Targeting function and cross-talk of bacterial Envelope proTein machineries

Periodic Reporting for period 2 - Train2Target (An integrated mulTidisciplinary appRoach towards a new generAtIon of aNtibiotics: Targeting function and cross-talk of bacterial Envelope proTein machineries)

Reporting period: 2019-01-01 to 2020-12-31

Antibiotics are essential tools in modern medicine. They are crucial for invasive surgery and treatments such as chemotherapy, moreover their use has reduced childhood mortality and increased life expectancy. However, the rapid increase of multidrug-resistant bacteria has reduced the arsenal clinically useful antibiotics, and the spectre of untreatable infections is becoming a reality. Antimicrobial resistance (AMR) has indeed been recently listed as one of the greatest threats to human health by the WHO. This scenario is especially alarming from Gram-negative bacteria which are also intrinsically resistant to many antibiotics due to their tripartite envelope structure and calls urgently for the development of novel antibacterial dugs.
The Train2Target is a multisectoral consortium gathering experts from academia and industry with the purpose of providing innovative solutions for antimicrobial drug discovery. The Gram-negative bacterial envelope is an essential structure, a formidable barrier that is difficult for antimicrobial drugs to penetrate and a place where resistance mechanisms may develop. It is also a well validated target for antimicrobial discovery and therefore a structure where identify new weaknesses for drug targeting.
In this context, the general objective of the Train2Target research programme is to dissect bacterial envelope biogenesis pathways to identify novel targets, to propose new leads and to train 15ESRs in all scientific and non-scientific aspects related to the drug discovery process.
Specific objectives of the Train2Target project are the following:
- Dissecting at the molecular level the function of the core machineries that assemble the different bacterial envelope layers ;
- Investigating how the activities of envelope machineries are orchestrated and coordinated to ensure appropriate growth of the different envelope layers during bacterial cell cycle;
- Developing innovative screening strategies/technologies to identify molecules inhibiting envelope biogenesis.
- Providing ESRs with transferable skills (i.e. commercialization of research results, IP management, ethical issues in research, communications, project management) as indispensable tools in the drug discovery process
The Train2Target consortium has timely hired 15 ESRs. According to the Train2Target programme the ESRs have received individual training at their host institution through the PhD programme in place and training sessions during the network-wide meetings that have been organised, as well as online webinars. Furthermore, several ESRs have had the possibility to participate in international and local conferences and benefit from external training at these events. At the time of writing this periodic report, PhD degrees have been awarded to 6 out of 15 ESRs. For the remaining ESRs completion, submission of theses and award of PhD degree is scheduled according the rules of enrolling institutions.
Three Train2Target annual meetings on September 2017, October 2018 and October 2019 have been organized. In these meetings guest speakers have given lectures on envelope biogenesis and AMR related issues and the 15 ESRs have had the opportunity to report on the progress of their research activities and to practice their presentation skills. Two webinars on “Envelope biogenesis and signalling systems” and on “Research data management” mandatory for all ESRs and open for the consortium have been organised. A lndustry Course on “Antibacterial Drug Discovery & Development” has been organised by the Beneficiaries industries of the consortium in February 2019. In May 2019 the “Funding & Career” workshop has been organised by UNIBR and UCL-DeDuve beneficiaries.
The scientific work has been performed according to three scientific work packages (WPs). In WP1 ESRs analysed the assembly dynamics of Lpt and Bam multiprotein envelope machineries and developed biophysical (FRET) and genetic (TraDIS) tools to unravel both protein-protein and genetic interactions during bacterial cell cycle. New targets for antibacterial design and synthesis have been uncovered. In WP2 ESRs explored the cross-talk between the different multiprotein envelope machineries (Lpt, Bam, Elongasome, Divisome) and uncovered novel signalling mechanisms that not only orchestrate their functioning but are also required to maintain envelope homeostasis. This is an important result as targeting envelope homeostasis could lead to development of molecules that act as potentiator of current antibiotics. In WP3 ESRs developed smart screening assays to target protein or protein complexes implicated in envelope growth or its regulation and performed metabolomic analyses on poorly explored taxa to uncover new biosynthetic capabilities. Results from these studies led to the identification of new potent hits inhibiting envelope synthesis and novel secondary metabolites with antibacterial properties. These molecules are currently progressed by the respective beneficiaries. Dissemination of Train2Target results has been so far achieved through 23 peer reviewed publications on high impact journals. At the time of writing 10 additional manuscripts reporting T2T results have been submitted or are under review. Results have also been disseminated through ESRs attendance at international meetings and outreach activities.
Overall, despite the critical situation given by Covid-19 pandemic the network has been capable to successfully conclude the project and to achieve the set milestones.
Research methods employed by the Train2Target go beyond the state of the art by covering a wide spectrum of innovative techniques in genetics, biochemistry, structural biology, biophysics and screening. Moreover, the multidisciplinary nature of the Train2Target research and training programme has endowed the ESRs with the knowledge base and skills set to become the future leaders in the field of antimicrobial discovery and development. Overall the Train2Target programme successfully provided the ESRs with the necessary skills to become attractive candidates for top universities, research centres and industries active in the field of antimicrobial drug discovery.
Given the huge economic burden caused by infections provoked by multi-resistant strains in Europe and worldwide, the development of novel therapeutic options will have an important positive impact on our society.
Train2Target Consortium Meeting