MICROBIOTIX, INC. — Department of Health and Human Services SBIR Phase II: NIAID

Description

DESCRIPTION provided by applicant Multi drug resistance MDR in Gram negative pathogens including the Enterobacteriaceae and Pseudomonas aeruginosa poses a significant threat to our ability to effectively treat infections caused by these organisms A major component in the development of the MDR phenotype in Gram negative bacteria is overexpression of RND type efflux pumps which actively pump antibacterial agents and biocides from the periplasm to the outside of the cell Clearly bacterial efflux pumps are an important target for developing novel antibacterial treatments that increase the potency of existing antibiotics and decrease the emergence of MDR bacteria In preliminary studies we identified a novel pyranopyridine MBX that is a potent inhibitor of AcrAB TolC the major efflux pump of E coli and other Enterobacteriaceae MBX enhances the activity of fluoroquinolones FQs and lactam antibiotics against E coli but does not exhibit antibacterial activity alone nor is it cytotoxic In Phase I we synthesized MBX analogs and evaluated them for potency selectivity spectrum of activity and in vitro ADME properties to identify compounds with improved activity and drug like properties and to generate a molecular activity map for this series As a result of this research we have identified analogs that exhibit a andgt fold increase in antibiotic potentiation and satisfy the criteria for successful completion of the Phase I milestones The overall goal of this Phase II project is to further develop the pyranopyridine series to identify in vivo validated lead compounds that are suitable for IND enabling preclinical studies In Phase II we will utilize an approach that combines structure based drug design with medicinal chemistry to design and synthesize analogs with improved spectrum of activity and ADMET properties while maintaining potency against efflux by the Enterobacteriaceae To facilitate this approach and probe the mechanism of action we will generate a three dimensional structure of MBX and analogs bound to AcrB Analogs will be evaluated in a panel of secondary assays to prioritize compounds for efficacy and pharmacokinetic PK studies in animals In addition the data derived from these assays will inform the design of additional compounds Through an iterative process of compound design and evaluation we anticipate that we will identify in vivo validated lead compounds with favorable PK and in vivo efficacy In Phase III these efflux pump inhibitors will be developed for use in combination with levofloxacin LEV or piperacillin tazobactam PIP TAZ as an adjunctive therapy for urinary tract and bloodstream infections as the first therapeutic indications for this inhibitor series These adjunctive therapis represent a significant improvement over single agent therapies because they will provide the following benefits increased antibiotic efficacy at lower concentrations and decreased evolution of resistance The Specific Aims for Phase II are as follows Aim Chemically optimize the pyranopyridine series to generate lead compounds for animal safety and efficacy testing Aim Prioritize analogs by potency spectrum selectivity favorable in vitro ADMET properties Aim Determine the three dimensional structure of pyranopyridines bound to AcrB and biochemical mechanism Aim Evaluate acute toxicity pharmacokinetics and efficacy of lead compounds in animal models PUBLIC HEALTH RELEVANCE The AcrAB TolC efflux pump plays an important role in the intrinsic resistance of many important bacterial pathogens to many of the antibiotics that are used to treat infections caused by these organisms Increased production of this efflux pump can result in multidrug resistance MDR Inhibition of this efflux pump will result in increased efficacy of antibiotic therapies and decreased evolution of resistance In this project we will develop a series of novel efflux pump inhibitors the pyranopyridines to show in vivo efficacy with the ultimate goal of developing a novel class of drugs that can be used in combination with existing antibiotics to increase their clinical efficacy in the treatment of Gram negative infectios