P3: Design and synthesis of simplified polyketide antibiotics as improved antibacterial agents

It has been estimated that more than 60% of new chemical entities introduced as drugs during the last two decades are or were inspired by natural products. However, structurally complex and consequently less accessible metabolites, which do not adhere to the conventional Ro5, have received little attention as pharmaceutical lead compounds.

Polyketide antibiotics present important pharmaceutical lead compounds. However, structurally complex and consequently less accessible metabolites have received less attention. They defy common drug-like properties as expressed by Lipinski’s rule of 5 and supply issues provide a severe limitation, which often cannot be resolved by total synthesis. Consequently, simplified and thus more readily accessible analogs with equipotent or improved profiles are highly desirable.

This joint project will evaluate and advance the antibacterial potential of complex (macrocyclic) polyketide antibiotics. It will initially focus on the lysolipins and vancoresmycin. The lysolipins demonstrate inhibitory concentrations (MIC) in the low nanomolar range against Gram-positive pathogens and also show higher, but still nanomolar MIC against Gram-negative microorganisms. They interact with the bacterial membrane. Vancoresmycin in turn is extremely active against a broad range of pathogenic Gram-positive bacteria. It was proposed to target the bacterial membrane resulting in membrane depolarization, however molecular details are still elusive. In this project, carefully designed simplified analogs of these polyketide antibiotics will be obtained by versatile and modular coupling strategies and their detailed mode of action will be unraveled.

The Menche group has a strong background in the total synthesis and analytics of complex polyketides and in close cooperation also within this consortium has designed simplified and more readily available polyketide analogs with potent biological properties and synthesized them by tailored synthetic strategies. A. Müller in turn is experienced in mode of action (MoA) analyses and target identification of antibiotics and compounds with anti-virulence activity.

This project will closely collaborate with several projects to unravel the biological potential and MoA of polyketides antibiotics, including P5, P6 and P9 based on proven track records of previous collaborations of the respective PIs. Moreover, P3 will be interconnected with P4, both working on macrocycles. P3 will additionally provide antibacterial susceptibility testings for compounds synthesized by other groups of the RTG and (initial) MoA analyses will be performed for promising hit compounds.