The goal of this project is to develop a new class of urea-depsipeptide (UDEP) antibiotics to treat prosthetic joint infections (PJI). UDEPs kill bacteria through activation of the ClpP protease, causing cells to self-digest. This unique activating mechanism allows UDEPs to kill biofilms and non-growing persister cells, which are prevalent in PJI and explain why current antibiotics are largely ineffective. Current therapies involve weeks to months of antibiotic treatment, debridement surgeries, and medical device replacement. UDEPs have the potential to minimize surgical interventions due to PJI and improve patient care. PJI are primarily caused by the Gram-positive pathogens Staphylococcus aureus and epidermidis and the UDEPs are potently active against these pathogens, including multi-drug resistant strains. A recent advance in our UDEP medical chemistry program yielded a new compound which has improved safety, solubility, and bone penetration compared to first generation UDEPs. A preliminary study found that the compound was effective in a K-wire femur medullary canal implant model of PJI, which is known to be difficult to treat. In this project, we will evaluate if the compound is an acceptable pre-clinical candidate for PJI by testing it in a series of in vitro and in vivo studies focused on this indication. Specifically, the aims are to 1) scale up the compound; 2) determine the microbiological and biofilm killing effect against the main pathogens isolated from PJI; and 3) determine the efficacy of the compound in mouse and rabbit models of PJI. Public Health Relevance Statement When a hip or knee replacement becomes infected, antibiotics are used in combination with surgery to treat the infection. Typically, the artificial joint must be removed and replaced. The purpose of this project is to develop a new antibiotic that will minimize surgeries and improve the outcome of patients with infected joint replacements.
Project Terms: Amputation ; Anti-Infective Agents ; Anti-Infective Drugs ; Anti-Infectives ; Anti-infective Preparation ; AntiInfective Drugs ; AntiInfectives ; Antiinfective Agents ; communicable disease control agent ; Antibiotics ; Antibiotic Agents ; Antibiotic Drugs ; Miscellaneous Antibiotic ; Combined Antibiotics ; Antibiotic Combinations ; Antibiotic Drug Combinations ; Bacteremia ; bacteraemia ; Bacteria ; Biological Assay ; Assay ; Bioassay ; Biologic Assays ; bone ; Cefazolin ; cell growth ; Cellular Expansion ; Cellular Growth ; Cell Wall ; Cells ; Cell Body ; Chemistry ; Pharmaceutical Chemistry ; Medicinal Chemistry ; Pharmaceutic Chemistry ; Coagulase ; Debridement ; Drug Combinations ; Pharmaceutical Preparations ; Drugs ; Medication ; Pharmaceutic Preparations ; drug/agent ; Femur ; Patient Care ; Patient Care Delivery ; Goals ; Healthcare Systems ; Health Care Systems ; Human ; Modern Man ; In Vitro ; Infection ; Joint Prosthesis ; artificial joint ; prosthetic joint ; Joints ; Medical Device ; Microbiology ; mortality ; Mus ; Mice ; Mice Mammals ; Murine ; Nafcillin ; Nafcil ; Nallpen ; Naphthamidopenicillin ; Orthopedics ; Orthopedic ; Orthopedic Surgical Profession ; Patients ; Peptide Hydrolases ; Esteroproteases ; Peptidases ; Protease Gene ; Proteases ; Proteinases ; Proteolytic Enzymes ; Drug Kinetics ; Pharmacokinetics ; Phosphoric Monoester Hydrolases ; Phosphatases ; Phosphohydrolases ; Phosphomonoesterases ; Physicians ; Placebos ; Sham Treatment ; sham therapy ; Prodrugs ; Drug Precursors ; Pro-Drugs ; Proteins ; Oryctolagus cuniculus ; Domestic Rabbit ; Rabbits ; Rabbits Mammals ; Relapse ; Rifampin ; Benemycin ; Rifadin ; Rifampicin ; Rimactane ; Role ; social role ; Safety ; Solubility ; Staphylococcus aureus ; S aureus ; S. aureus ; Staph aureus ; Staphylococcus epidermidis ; S epidermidis ; S. epidermidis ; Enterococcus faecalis ; E faecalis ; E. faecalis ; S faecalis ; S. faecalis ; Streptococcus Group D ; Streptococcus faecalis ; Testing ; Thigh structure ; Thigh ; tibia ; Titanium ; Ti element ; Translations ; United States ; Urea ; Carbamide ; Elaqua XX ; Urea Carbamide ; Ureaphil ; Vancomycin ; Generations ; Microbial Biofilms ; biofilm ; Catheters ; knee replacement arthroplasty ; Knee arthroplasty ; Knee joint replacement operation ; Knee replacement ; Total Knee Replacement ; total knee arthroplasty ; Specialist ; Prosthesis ; Prosthetic device ; Prosthetics ; base ; improved ; Replacement Arthroplasty ; Arthroplasty ; Joint Prosthesis Implantation ; joint arthroplasty ; joint replacement ; Penetration ; Physiological ; Physiologic ; Medical ; Series ; Failure ; Multi-Drug Resistance ; Multidrug Resistance ; Multiple Drug Resistance ; Multiple Drug Resistant ; Resistance to Multi-drug ; Resistance to Multidrug ; Resistance to Multiple Drug ; Resistant to Multiple Drug ; Resistant to multi-drug ; Resistant to multidrug ; multi-drug resistant ; multidrug resistant ; Collaborations ; cleaved ; Cleaved cell ; Antibiotic Treatment ; bacterial disease treatment ; bacterial infectious disease treatment ; Antibiotic Therapy ; programs ; Hip Prosthesis Implantation ; hip arthroplasty ; hip joint replacement ; hip replacement ; hip replacement arthroplasty ; Scientist ; Immunes ; Immune ; implant material ; subdermal ; subcutaneous ; Route ; Operative Procedures ; Surgical ; Surgical Interventions ; Surgical Procedure ; surgery ; Operative Surgical Procedures ; Surgeon ; phosphate ester ; Zyvox ; Linezolid ; Structure ; economic impact ; Teflon ; Devices ; Acne ; Abscission ; Extirpation ; Removal ; Surgical Removal ; resection ; Excision ; Depsipeptide Antibiotic ; Depsipeptides ; Pharmacodynamics ; Modeling ; MRSA ; Methicillin Resistant S Aureus ; Methicillin Resistant S. Aureus ; methicillin-resistant S. aureus ; methicillin resistant Staphylococcus aureus ; preventing ; prevent ; Data ; in vivo ; Antimicrobial Effect ; anti-microbial effect ; Enrollment ; enroll ; Patient-Focused Outcomes ; Patient outcome ; Patient-Centered Outcomes ; Nutritional ; nutritious ; Process ; Development ; developmental ; pre-clinical ; preclinical ; design ; designing ; novel strategies ; new approaches ; novel approaches ; novel strategy ; scale up ; Resistance development ; Resistant development ; developing resistance ; pathogen ; Implant ; mouse model ; murine model ; standard of care ; resistant strain ; resistance strain ; in vitro testing ; 3D Print ; 3-D print ; 3-D printer ; 3D printer ; 3D printing ; three dimensional printing ; resistance frequency ; trial design ; joint infection ; joint sepsis ; septic joint ; improved outcome ; Primary Infection ; clinical candidate ; antibiotic tolerance ; tolerance to antibiotics ; tolerate antibiotics ; mortality risk ; death risk ;
