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.
