The overall goal of this project is to develop novel bone-targeted conjugates of clinically relevant antibiotics for the treatment of osteomyelitis. These compounds are new chemical entities built from known and approved antibiotics and bisphosphonates, which are connected via biodegradable phosphate linker. The design of these drugs exploits the high bone affinity of bisphosphonates to target the conjugate directly to the site of bone infection where both drugs are released. Proof-of-concept of this drug design as applied to cancer induced bone disease has been demonstrated in humans. We hypothesize that this design will enable the concentration of antibiotic in bone to currently unachievable levels while also reducing systemic exposure. Such conjugates may have a wider therapeutic range than currently available therapies, and as an added benefit, the drugs also strengthen the bones and may reverse the deterioration of bone, associated with infection. The proposed studies will enable the preparation of a four novel conjugates that will be characterized in vitro and assessed for efficacy in a mouse model of osteomyelitis. The specific aims of this project are: (1) Develop synthetic methods and make sufficient amounts of four conjugates composed of one of two bisphosphonates classes (etidronate or ibandronate) and two antibiotics (ciprofloxacin or clindamycin); (2) Demonstrate efficacy in a luciferase based mouse model of osteomyelitis, reduction or elimination of bone localized staphylococcus aureus and (in a parallel model) psuedomonous aeruginosa and assess the microarchitecture of bone with histology, imaging and markers of bone turnover. The successful completion of this Phase I project will guide the further development of this promising concept, identify a lead compound to be carried into FDA required studies for investigational new drug approval, and lead to eventual clinical application. It is anticipated that this technology will ultimately result in therapeutic agents that will significantly improve osteomyelitis patient care resulting in decreased morbidity and reduced amputations and reduced antibiotic related toxicities as well as reduce the risk of infection for routine surgery and bone-exposed trauma patients.
Public Health Relevance Statement: Project Narrative Relevance: Infection of bone is a risk any time the bone is exposed from trauma or surgery, or in cases of vascular insufficiency, diabetes, sickle cell and systemic infection. Treatment involves long-term high-dose intravenous antibiotics and often surgical debridement; despite such aggressive therapy, recurrence and development of chronic osteomyelitis are common, and amputation may be required. The long-term goal of this project is to meet the great need to prevent and treat bone infection by developing bone-targeted therapies designed to deliver and concentrate antibiotic drugs at the sites of bone infection, such as osteomyelitis.
Project Terms: Address; Adverse event; Aerobic; Affinity; aggressive therapy; Amputation; Anaerobic Bacteria; Anti-Infective Agents; Antibiotic Therapy; Antibiotics; Antineoplastic Agents; Automobile Driving; Bacterial Model; base; Binding; bisphosphonate; Blood Circulation; Blood Vessels; bone; Bone Diseases; Bone Resorption; bone turnover; Cancer Patient; Chemicals; Chronic; Ciprofloxacin; Clindamycin; clinical application; clinically relevant; Cytarabine; Debridement; design; Deterioration; Development; Diabetes Mellitus; Dose; Drug Approval; Drug Design; Drug Kinetics; Elements; fluorodeoxyglucose positron emission tomography; Fluoroquinolones; Generations; Goals; Growth; Histology; Histopathology; Human; Ibandronate; imaging biomarker; improved; In Vitro; in vitro testing; in vivo; Infection; inorganic phosphate; Intravenous; Investigational Drugs; Lead; Lesion; lincosamide; Link; Luciferases; Malignant Neoplasms; Measurement; Metastatic Neoplasm to the Bone; methicillin resistant Staphylococcus aureus; Methods; microCT; Modeling; Morbidity - disease rate; mouse model; novel; Nucleosides; Operative Surgical Procedures; Organism; Osteomyelitis; Patient Care; Patients; Pharmaceutical Preparations; Phase; Phase I Clinical Trials; Preparation; prevent; Procedures; Property; Recurrence; Renal clearance function; Reporting; Risk; scale up; Serious Adverse Event; Serum; Sickle Cell; Site; Staphylococcus aureus; success; Systemic infection; systemic toxicity; targeted treatment; Technology; Testing; Therapeutic; Therapeutic Agents; therapy design; Time; Toxic effect; Trauma; Trauma patient; Work; X-Ray Computed Tomography
