Antibiotics for Recalcitrant Infection

DESCRIPTION provided by applicant The goal of the project is to develop a therapeutic capable of sterilizing recalcitrant chronic infections such as deep seated abscess osteomyelitis endocarditis and biofilms of indwelling devices Many of these infections are essentially untreatable and lead to substantial morbidity and mortality In many cases recalcitrance of an infection is not caused by drug resistance Rather a slow growing biofilm population harbors stationary phase and dormant persister cells that are highly tolerant to killing by antimicrobials When antibiotic concentration drops these cells can grow and repopulate the biofilm In Gram positive S aureus it appears that a stationary culture is made mostly of drug tolerant cells which are virtually insensitive to killing by traditional antibiotics There are many independent redundant mechanisms of persister formation and these specialized survivor cells do not have a realistic target which could be exploited for drug development In order to act all existing bactericidal antibiotics require active targets which they corrupt We reasoned that persisters could be killed if a small molecule could simultaneously activate and corrupt a cellular target We find that acyldepsipeptide ADEP activates the ClpP protease in dormant persisters forcing the cell to self digest In order to diminish resistance development ADEP was combined with rifampicin The combination completely sterilized a deep seated biofilm infection of S aureus in a neutropenic mouse model after a single dose The best conventional antibiotics alone or in combination had very little effect This model emulates the most difficult to treat chronic infection in immunocompromised patients In this project we will identify the most promising sterilizing combinations of drugs Combinations will be evaluated for PK PD and efficacy using a deep seated neutropenic thigh model of MRSA infection and in an in vivo biofilm tissue cage model Once validated the combination therapeutic will enter into preclinical investigation in Phase II leading to an IND and subsequent clinical trials of the drug PUBLIC HEALTH RELEVANCE The goal of the project is to develop a therapeutic capable of curing currently untreatable chronic infections Bacterial pathogens are not susceptible to killing by traditional antibiotics when they are in a non growing inactive state This makes it very difficult to treat diseases such as infective osteomyelitis or endocarditis We have identified a compound capable of killing inactive cells and we will develop this compound into a therapeutic