Natural product inspired antibacterials with unique ribosomal binding

Project Summary The long term objective of this project is to develop a new class of broad spectrum antibiotics focused on Gram negative bacteria Inspired by a natural product this class targets an unexploited binding site of the bacterial ribosome With ever increasing reports of resistance to frontline therapies addressing Gram negatives there is a critical need for new therapies yet very little can be found in the development pipeline As a result any new therapeutic that targets Gram negative bacteria will address an unmet medical need A viable approach to discover new therapeutic leads is re evaluation of existing but under scrutinized classes of natural products Through this approach a natural product scaffold was identified as a lead for a program directed toward antibiotics for tuberculosis Initial evaluation of activity against other bacteria indicated that the antibacterial spectrum was limited to Mycobacterium spp However based on the chemical structure and related compounds we expected to be able to generate analogs with more broad spectrum activity In collaboration with Tom Steitzandapos s lab at Yale the structure of the initial scaffold and two analogues bound to the ribosome were recently solved The structural studies revealed that the natural product lead and analogues bind to a highly conserved region of the peptidyl transferase center PTC in a manner that appears to convey prokaryotic selectivity and which has not been exploited in current therapeutics Targeting this highly conserved region is expected to lead to slow rates of resistance This structural information was used to generate two more potent analogues with favorable physicochemical properties In a very preliminary SAR campaign of andlt compounds we re engineered a portion of our lead scaffold for both synthetic simplicity and stability to provide two analogs that introduce activity beyond Mtb to both MRSA and E coli and do not exhibit cytotoxicity to eukaryotic cells IC andgt M Since the original submission analogs active against K pneumoniae including a drug resistant strain have been produced This two year Phase I project will demonstrate feasibility for developing this lead scaffold as an effective broad spectrum antibiotic using the following aims Aim will develop new compounds to optimize potency and further refine the SAR using the co crystal structures to guide medicinal chemistry efforts Aim will define biochemical and microbiological activity of analogs by evaluating activity against prokaryotic and eukaryotic protein synthesis and a panel of bacteria representing Gram negative and positive organisms including antibiotic resistant strains Preliminary ADME Tox will be evaluated in vitro in Aim Phase I will culminate in Aim determining the MTD to guide dosing that will be used to demonstrate proof of concept reduction in bacterial burden in a mouse thigh infection model Project Narrative Bacterial resistance to current antibiotics continues to increase in both hospital and community settings and is recognized as a major Global health crisis This project will develop novel antibiotics that bind a clinically undrugged site of the ribosome that confers selectivity to bacteria while not affecting mammalian protein synthesis Given the dearth of new agents against Gram negative pathogens this project will address an unmet medical need