Bone targeted antimicrobials for the treatment of diabetic foot related infections and osteomyelitis

ABSTRACTDiabetes Mellitus is a serious chronic disease in which the physiological homeostatic controls in the body becomes less responsive to changing blood glucose levelsIn Type II diabetes the body makes little or no insulinthe hormone responsible for reducing blood glucose levelsor the mechanisms down stream of insulin become unresponsive to the insulin producedType II diabetes is the most prevalent form of the disease accounting for overof the andgtmillion people in the US with the diseaseDiabetic peripheral neuropathy is one of the primary complications of diabetesand up toof diabetic patients will present with this issueThis leads to problems with cutaneous wound healing and to ulcerations and advanced infections particularly in the footDiabetic Foot InfectionsDFIand associated diabetic foot osteomyelitisDFOare serious infections which can lead to very high levels of sequelae including amputationThe DFO infections are complex and difficult to treat bone infections often requiring long term antibiotic treatment and surgery !Here we lay out a potential therapeutic solution to this problem based on the use of bisphosphonateBPantimicrobial conjugates that will target to bone and release their antimicrobial payload at the bone surfaceOur strategy will directly target the bacterial biofilm reservoir on the bone and lower the amount of systemic drug treatment neededlimiting extra osseous exposureOur preliminary results support testing the feasibility of using this highly innovative strategy for the treatment of DFOTo support establishing the feasibility of this approach we set out three specific aimswe will synthesize novel drug candidates based on an advanced newer generation fluoroquinolonemoxifloxacinMOXIincluding several linkage strategies to tune the bone target and release kineticswe will test these BP MOXI conjugates in vitro using hydroxyapatite bone mineral models of biofilm infectionsandwe will test the conjugate with the most favorable release kinetics and bactericidal activityfrom aim twoin a type II diabetic mouse model of osteomyelitisThere is a great unmet medical need for novel and effective treatments for DFOand we believe that our novel and innovative BP MOXI conjugatethat is capable of releasing MOXI directly into the site of bone infectionwill provide a transformative treatment for this diseaseHere we lay out the strategy to prove the feasibility of this approach!PROJECT NARRATIVE Diabetic Foot Osteomyelitis is often an untreatable disease that can require amputation of the affected limbOverpatients per year are admitted into hospitals with diabetes related bone infections leading to poor prognosis and significant morbidityWe propose a transformative therapeutic solution to this unmet medical need with our design of an innovative highly bone specific antimicrobial drug series! !