Indentification and optimisation of novel anti-infective agents using multiple hit-identification strategies

Project Information

NovAnI

Grant agreement ID: 757913

DOI

10.3030/757913

Project closed

EC signature date 12 January 2018

Start date 1 February 2018

End date 31 January 2023

Funded under

• EXCELLENT SCIENCE - European Research Council (ERC)

Total cost

€ 1 499 367,00

EU contribution

€ 1 499 367,00

Coordinated by

HELMHOLTZ-ZENTRUM FUR INFEKTIONSFORSCHUNG GMBH
Germany

Periodic Reporting for period 4 - NovAnI (Indentification and optimisation of novel anti-infective agents using multiple hit-identification strategies)

Reporting period: 2022-08-01 to 2023-01-31

Summary of the context and overall objectives of the project

The silent pandemic of antibiotic resistance is a global health threat affecting millions of people worldwide. It is caused by natural mechanisms of pathogen defense and by the excessive and incorrect use of antibiotics in humans and in animal husbandry. As a result, the treatment of a wide variety of infections, for example those caused by Mycobacterium tuberculosis, is becoming increasingly problematic. Therefore, the development of new antibacterial agents as innovative therapeutics with novel mechanisms of action is urgently needed. To achieve this ambitious goal, our strategy focused on inhibiting biologically highly relevant, under-explored enzymes and transporters in such pathogens. These are the so-called targets DXS, ECF-T and DnaN. These target proteins are involved in the biosynthesis and import of essential substances such as vitamins into the pathogen, and their inhibition should lead to the halt of their proliferation and ultimately their death. To identify and further develop such inhibitors, we pursued innovative and unconventional strategies during the ERC-based funding. In all subprojects, we have been able to identify and further develop potent inhibitors. We have also developed techniques that can be used to accelerate the future development of our compounds. The observed activities relate not only to on-target inhibition, but also to antibacterial activities, e.g. against Mycobacterium tuberculosis, and we obtained promising in vitro ADMET and in vivo PK data. Together, these data demonstrate the potential of our compounds to become clinically used anti-infectives with an unprecedented mode of action for the treatment of serious infectious diseases such as malaria and tuberculosis.

Work performed from the beginning of the project to the end of the period covered by the report and main results achieved so far

We focused from the start of the funding period on identifying novel inhibitors to address our main targets, DXS, ECF-T, and DnaN. These three selected targets play important roles in the biosynthesis and import of essential substances such as vitamins within and into various pathogens such as M. tuberculosis. For hit identification, we employed innovative and unconventional strategies, including protein-templated methods called dynamic combinatorial chemistry (DCC) and kinetic target guided synthesis (KTGS). Furthermore, biophysical and also computational methods were used for the (virtual) screening of compound libraries. We have succeeded in identifying numerous hit compounds for all targets. The subsequent stepwise optimization of the hits through rational design and organic synthesis was accompanied by a thorough biological evaluation of the novel compounds. Valuable structure–activity relationships were established. Our optimization efforts resulted in compounds showing significant binding and inhibition of our three target enzymes as well as promising antibacterial activities against pathogens such as Mycobacterium tuberculosis. Furthermore, we obtained promising in vitro ADMET and in vivo PK data. These results have become part of numerous peer-reviewed publications in recent years, and have been presented at scientific conferences by means of oral presentations and posters. Two patent applications are in preparation.

Progress beyond the state of the art and expected potential impact (including the socio-economic impact and the wider societal implications of the project so far)

Using innovative and unconventional strategies, we have discovered novel compounds capable of inhibiting our biologically important antibacterial targets. Likewise, the other results obtained from biological profiling, as well as the refined and new assay systems established in this context, are advances that go beyond the state of the art that prevailed prior to the ERC grant. Importantly, the projects do not come to an end after the funding has finished, but continue to be pursued intensively, also thanks to further support from the ERC (PoC grant) as well as dedicated Helmholtz funding. This additional funding will enable us to further advance the most promising (especially ECF-T and DnaN) inhibitors on the translational path and to obtain an optimized lead compound with which an in vivo proof of concept can be achieved. In this context, two patents currently being drafted will help protect our acquired intellectual property. The third target DXPS is also being continued as part of the ITN MepAnti.

DXS_drDXS_1

Chemistry A European J - 2020 - Mancini