New antibiotics targeting fatty acid biosynthesis

DESCRIPTION (provided by applicant): Antibiotic resistant pathogens, such as methicillin-resistant Staphylococcus aureus, are a significant public health problem which is compounded by the slow rate of development of new antibiotics. Investigators at Merck Research Laboratories recently reported on the isolation and activity of two new natural products, platensimycin and platencin. These were an exciting results as the compounds acts in a novel manner: they are inhibitors of key steps (FabH and FabF) in fatty acid biosynthesis. We have an excellent opportunity to leverage our experience in synthetic chemistry, bioassay and crystallography to generate a select panel of structurally much simpler platensimycin/platencin analogs to define the key pharmacophore and improve activity and spectrum of activity. The development of dual FabH/F inhibitors is a significant goal as antibiotics that target two steps in a biosynthesis pathway are less likely to be compromised by emerging resistance. In this Phase I STTR feasibility study we will determine if structurally simplified platensimycin/platencin analogs have promise through: Aim 1: Leveraging the synthetic experience of the Wright group at The University of Connecticut we will generate a select array of platensimycin/platencin analogs using the cyclocondensation of furan and perhalocyclopropene derivatives as the key synthetic transformation. Aim 2: Promiliad Biopharma will conduct extensive bioassay of the new derivatives against Gram positive bacteria, Gram negative bacteria, fungi and Human cell lines to determine MIC and IC50 values for growth inhibition. In vitro inhibition data for the new compounds against the target proteins FabF/H will be obtained. We will also measure the frequency of resistance in S. aureus. Aim 3: Leveraging the X-ray crystallographic expertise of the Anderson group at The University of Connecticut, active platensimycin/platencin analogs will be co-crystallized with both FabF and FabH to obtain high resolution structural information which will drive further medicinal chemistry efforts. The synthetic, biological and structural data forthcoming will allow us to determine if our approach has merit and will guide us in further optimization and development of platensimycin/platencin analogs (Phase II). PUBLIC HEALTH RELEVANCE: Antibiotic resistance among common bacterial pathogens is a serious public health problem because it compromises our ability to treat many infectious diseases. The resistance problem has been compounded by the lack of discovery of new antibiotics, particularly those that act in novel ways. Such new compounds are critically needed as resistance to older antibiotics, and even their newer counterparts, is growing. The goal of our work is to develop a new set of antibacterial compounds, platensimycin/platencin derivatives, as agents that are active against bacterial pathogens. In this work we will make use of synthetic chemistry, bioassay and protein crystallography to improve on the natural product antibiotics platensimycin and platencin. At the end of this project we will know if structurally simpler platensimycin analogs can be developed into useful drugs.