Synthesis, biological evaluation and structure-activity relationships inhibitors of lipid A biosynthesis

• Applicant: Professor Dr. Ralph Holl
• Subject Area: Pharmacy
• Term: from 2014 to 2018
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 258378720

The growing number of multiresistant bacteria urgently necessitates novel antibiotics with a so far unexploited mechanism of action. The inhibition of the biosynthesis of lipid A represents a starting-point for the development of antibiotics against Gram-negative bacteria. The enzyme LpxC catalyzes the first committed step of lipid A biosynthesis and could be validated as an antibacterial drug target. Starting from LpxC inhibitors which were synthesized in our group, conformationally restricted as well as flexible benzyloxyacetic acid derivatives with an optimized inhibitory activity against the deacetylase, an improved antibacterial activity against a broad spectrum of Gram-negative bacteria and a high metabolic stability shall be developed. Supported by molecular docking studies, the zinc-binding group, the central ether core and the lipophilic side-chain, which represent the three main structural elements of the inhibitors, will be independently varied and the resulting compounds will be tested for their antibiotic activities. Relationships between their inhibitory activity against isolated LpxC and their structure (including stereochemistry) will be established. As the LpxC enzyme assay requires the expensive natural substrate of LpxC, an artificial substrate shall be deduced from the structure of the optimized inhibitors and will be optimized for its use in the enzyme assay. Additionally, the preparation of E. coli LpxC as well as of the enzyme from other Gram-negative bacterial species shall be facilitated by employing autodisplay.In order to inhibit lipid A synthesis more effectively, inhibitors of LpxA, another enzyme of the biosynthesis, will be developed. For this purpose virtual screening will be employed and the synthesis of peptidomimetics is envisaged.

• DFG Programme: Research Grants