Phase I Amount
$1,218,307
?The goal of the project is to develop a therapeutic against vancomycin resistant enterococcus (VRE). These infections are a serious health concern because antibiotic resistance has gotten to the point where there are few or no effective treatment options available. For the enterococci, resistance is inherently linked to tolerance - th ability of the pathogen to survive in the presence of bactericidal antibiotics. The enterococci survive typically lethal concentrations of antibiotics, causing an infection associated with significant morbidity, mortality and costs. We have created a novel series of acyldepsipeptide (ADEP) antimicrobials that activate the ClpP protease, which leads to protein degradation, overcoming drug tolerance and resulting in cell death. When a panel of VRE clinical isolates was tested against these new antimicrobials, no cross resistance with antibiotics used to treat this pathogen was detected, as expected for a novel mechanism of action. The compounds were potently bactericidal against stationary phase and biofilms of VRE, however in vitro resistance occurred due to null mutations in the ClpP protease. Knowing the potential of these antimicrobials to overcome drug tolerance, we combined them with traditional antibiotics and did not detect resistance. ClpP null mutants exhibit slow growth, heat sensitivity, increased susceptibility to many antibiotics and are avirulent in vivo. We have optimized the pharmacokinetics (PK) and other important properties of the series. We will perform detailed in vitro and in vivo validation of safety, PK, and efficacy against VRE in order to identify a pre-clinical lead and suitable backup candidate from among our proprietary series of ADEP analogs. Once validated, we will be well positioned to partner the technology for development, leading to an IND and clinical trials of the drug.
Public Health Relevance Statement: Public Health Relevance: The goal of the project is to develop a therapeutic capable of treating vancomycin resistant enterococcus infections. These pathogens exhibit high levels of tolerance and resistance to antibiotics, leaving few or no treatment options left. We have identified a compound capable of killing VRE, and we will develop this compound into a therapeutic.
Project Terms: Agar; Aminoglycosides; analog; Anti-Infective Agents; Antibiotic Resistance; Antibiotics; antimicrobial; Antimicrobial Resistance; Area Under Curve; attributable mortality; Autopsy; Back; Bacteria; bactericide; base; Binding Proteins; Biochemical; Biological Assay; Body Weight; Caco-2 Cells; Cardiovascular system; Cell Death; Cell Wall; Cells; chemical property; chemical stability; Clinical; Clinical Data; Clinical Trials; Clinical Trials Design; Collaborations; cost; Crystallization; cytotoxicity; Data; design; Development; Devices; Dose; Drug Kinetics; Drug Tolerance; effective therapy; Endocarditis; Enterococcus; Enterococcus faecalis; Enterococcus faecium; Enzyme Inhibition; Exhibits; Fiber; genotoxicity; Goals; Growth; Half-Life; Health; Heart; Heating; Hepatocyte; Hormonal; improved; In Vitro; in vivo; Infection; Intestinal Absorption; Kidney; Killings; Lactams; Lead; Left; Link; Liver; Lung; Maximum Tolerated Dose; Measurement; methicillin resistant Staphylococcus aureus (organism); Microbial Biofilms; Mitochondria; Modeling; Morbidity - disease rate; Mortality Vital Statistics; Mus; mutant; novel; novel therapeutics; null mutation; pathogen; Penicillins; Peptide Hydrolases; Pharmaceutical Chemistry; Pharmaceutical Preparations; Pharmacology; Phase; physical property; Plasma; Positioning Attribute; pre-clinical; Predisposition; Property; protein degradation; public health relevance; Rattus; receptor; research study; Resistance; Resistance development; resistance frequency; resistance mechanism; resistant strain; Resort; response; Rifampin; Safety; Saint Jude Children's Research Hospital; Septicemia; Series; Solubility; Specialist; Staphylococcus aureus; Streptomycin; Structure; technology development; Testing; Therapeutic; Thigh structure; tigecycline; Time; Tissue Cage; Tissues; Validation; Vancomycin; vancomycin B; Vancomycin resistant enterococcus
