Bone Targeted Antibiotics

Project Summary AbstractThe overall goal of this project is to develop novel bone targeted conjugates of clinically relevant antibiotics for the treatment of osteomyelitisThese compounds are new chemical entities built from known and approved antibiotics and bisphosphonateswhich are connected via biodegradable phosphate linkerThe 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 releasedProof of concept of this drug design as applied to cancer induced bone disease has been demonstrated in humansWe hypothesize that this design will enable the concentration of antibiotic in bone to currently unachievable levels while also reducing systemic exposureSuch conjugates may have a wider therapeutic range than currently available therapiesand as an added benefitthe drugs also strengthen the bones and may reverse the deterioration of boneassociated with infectionThe 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 osteomyelitisThe specific aims of this project areDevelop synthetic methods and make sufficient amounts of four conjugates composed of one of two bisphosphonates classesetidronate or ibandronateand two antibioticsciprofloxacin or clindamycinDemonstrate efficacy in a luciferase based mouse model of osteomyelitisreduction or elimination of bone localized staphylococcus aureus andin a parallel modelpsuedomonous aeruginosa and assess the microarchitecture of bone with histologyimaging and markers of bone turnoverThe successful completion of this Phase I project will guide the further development of this promising conceptidentify a lead compound to be carried into FDA required studies for investigational new drug approvaland lead to eventual clinical applicationIt 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