Narrow-spectrum Agents Acting against Helicobacter pylori

DESCRIPTION provided by applicant The goal of this project is to develop a therapeutic acting specifically against Helicobacter pylori the causative agent of peptic ulcer and gastric carcinoma Roughly every other person carries the pathogen and there are an estimated cases annually of active infection in the US The currently used triple therapy is a combination of a proton pump inhibitor and broad spectrum antimicrobials usually amoxicillin and clarithromycin A recent meta analysis of clinical data showed that treatment failure is An estimated of failures are due to antibiotic resistance Considering the total number of cases treatment failure is very high and H pylori is emerging as one of the most significant drug resistant pathogens and there is a considerable unmet need for novel treatments The obstacles for discovering a new therapeutic are formidable the last class of antibiotics acting against Gram negative species the fluoroquinolones was introduced years ago However we reasoned that it should be considerably easier to develop a narrow spectrum antimicrobial acting against H pylori Demands on a compound acting against a single target are less as compared to a broad spectrum which needs to inhibit many proteins of an orthologous group H pylori also have a large number of unique essential proteins which could serve as targets for new antimicrobials Poor permeability into Gram negative bacteria is another major obstacle for developing broad spectrum compounds but H pylori do not have a strong permeability barrier These considerations suggest that novel anti H Pylori compounds could be discovered in an HTS of commercial compounds libraries that failed to produce broad spectrum antimicrobials H pylori grow under microaerophilic conditions which are incompatible with standard HTS We were able to develop a first HTS against H pylori and a pilot screen produced a large number of diverse hits A major problem in HTS is a large number of toxic and promiscuous compounds We solved this problem with a counter screen against gut symbionts This resulted in leads that are specific against H pylori and will be free of side effects such as diarrhea associated with broad spectrum compounds that harm the gut flora Validation of the hits resulted in a potent lead MP with an MIC and MBC of g mL low cytotoxicity low resistance frequency reasonable ADME and an SAR making it suitable for further development The Phase I project will focus on closing SAR around the lead series which will inform medicinal chemistry optimization in Phase II Results from the pilot screen suggest that we have a validated discovery platform for selective anti H pylori compounds We will take advantage of this and will perform a larger HTS in order to identify a suitable back up series Iterative medicinal chemistry optimization will be combined with detailed validation of each series in Phase II in vitro validation will include potency spectrum of activity resistance development acid stabilit cytotoxicity absorption metabolic stability and plasma binding studies Candidates suitable for animal testing will emerge from medicinal chemistry using iterative design make test cycles aimed at multifunctional optimization of the microbiological pharmacologic and safety properties of each series Next compounds will undergo in vivo validation for suitable oral bioavailability and efficacy in a mouse model of H pylori infection Mechanism of action studies will be initiated for leads that exhibit animal efficacy The end result will be validated leads that will enable us o enter into a partnership with a Pharmaceutical Company for further preclinical development leading towards and IND clinical trials marketing a sales of a new selective therapeutic for peptic ulcer The aim of this project is to identify compounds to treat Helicobacter pylori infection H pylori cause acid reflux ulcers and stomach cancer However currently available therapeutics is broad spectrum antibiotics which cause high levels of resistance and unwanted side effects We will develop an antibiotic that specifically targets H pylori