SBIR-STTR Award

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.

Thesaurus Terms:
Abscess;Acute;Aminoglycosides;Anti-Bacterial Agents;Antibiotics;Antimicrobial;Antimicrobial Resistance;Bacteremia;Bactericide;Base;Canis Familiaris;Cells;Cellular Targeting;Chromosome Abnormality;Chronic;Clinical Trials;Collaborations;Combined Antibiotics;Daptomycin;Development;Disease;Dna Gyrase;Dose;Drops;Drug Combinations;Drug Development;Drug Discovery;Drug Resistance;Endocarditis;Endonuclease;Fiber;Fluoroquinolones;Frequencies (Time Pattern);Genotoxicity;Gentamicins;Goals;Human;Immune System;Immunocompromised Host;Implant;Implantable Device;In Vitro Model;In Vivo;Infection;Investigation;Killings;Lead;Linezolid;Meetings;Methicillin Resistant Staphylococcus Aureus (Organism);Microbial Biofilms;Modeling;Morbidity - Disease Rate;Mortality Vital Statistics;Mouse Model;Mus;Null Mutation;Osteomyelitis;Oxacillin;Pathogen;Peptide Hydrolases;Pharmaceutical Preparations;Pharmacodynamics;Pharmacology;Phase;Population;Population Heterogeneity;Pre-Clinical;Proteolysis;Public Health Relevance;Rattus;Refractory;Reporting;Resistance;Resistance Development;Rifampin;Risk-Benefit Assessment;Small Molecule;Staphylococcus Aureus;Stationary Populations;Sterilization;Survivors;Testing;Therapeutic;Thigh Structure;Tissue Cage;Toxic Effect;Work;

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 Statement:


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.

NIH Spending Category:
Antimicrobial Resistance; Emerging Infectious Diseases; Infectious Diseases

Project Terms:
Abscess; Acute; Aminoglycosides; Anti-Bacterial Agents; Antibiotics; antimicrobial; Antimicrobial Resistance; Bacteremia; bactericide; base; Canis familiaris; Cells; cellular targeting; Chromosome abnormality; Chronic; Clinical Trials; Collaborations; Combined Antibiotics; Daptomycin; Development; Disease; DNA Gyrase; Dose; Drops; Drug Combinations; drug development; drug discovery; Drug resistance; Endocarditis; endonuclease; Fiber; Fluoroquinolones; Frequencies (time pattern); genotoxicity; Gentamicins; Goals; Health; Human; Immune system; Immunocompromised Host; Implant; implantable device; in vitro Model; in vivo; Infection; Investigation; Killings; Lead; Linezolid; meetings; methicillin resistant Staphylococcus aureus (organism); Microbial Biofilms; Modeling; Morbidity - disease rate; Mortality Vital Statistics; mouse model; Mus; null mutation; Osteomyelitis; Oxacillin; pathogen; Peptide Hydrolases; Pharmaceutical Preparations; Pharmacodynamics; Pharmacology; Phase; Population; Population Heterogeneity; pre-clinical; Proteolysis; Rattus; Refractory; Reporting; Resistance; Resistance development; Rifampin; Risk-Benefit Assessment; small molecule; Staphylococcus aureus; Stationary Populations; Sterilization; Survivors; Testing; Therapeutic; Thigh structure; Tissue Cage; Toxic effect; Work