Bactericidal antibiotic for Vancomycin Resistant Enterococci

DESCRIPTIONprovided by applicantThe goal of the project is to develop a therapeutic against vancomycin resistant enterococcusVREThese infections are a serious health concern because antibiotic resistance has gotten to the point where there are few or no effective treatment options availableFor the enterococciresistance is inherently linked to toleranceth ability of the pathogen to survive in the presence of bactericidal antibioticsThe enterococci survive typically lethal concentrations of antibioticscausing an infection associated with significant morbiditymortality and costsWe have created a novel series of acyldepsipeptideADEPantimicrobials that activate the ClpP proteasewhich leads to protein degradationovercoming drug tolerance and resulting in cell deathWhen a panel of VRE clinical isolates was tested against these new antimicrobialsno cross resistance with antibiotics used to treat this pathogen was detectedas expected for a novel mechanism of actionThe compounds were potently bactericidal against stationary phase and biofilms of VREhowever in vitro resistance occurred due to null mutations in the ClpP proteaseKnowing the potential of these antimicrobials to overcome drug tolerancewe combined them with traditional antibiotics and did not detect resistanceClpP null mutants exhibit slow growthheat sensitivityincreased susceptibility to many antibiotics and are avirulent in vivoWe have optimized the pharmacokineticsPKand other important properties of the seriesWe will perform detailed in vitro and in vivo validation of safetyPKand efficacy against VRE in order to identify a pre clinical lead and suitable backup candidate from among our proprietary series of ADEP analogsOnce validatedwe will be well positioned to partner the technology for developmentleading to an IND and clinical trials of the drug