R01AI152067

Antifungal Antagonism as a Cause of Treatment Failure for Invasive Mycoses

An estimated 1.5 million people die each year from invasive fungal infections (IFIs), with millions more afflicted by debilitating mucosal and subcutaneous mycoses. Current antifungal therapies have serious deficiencies including limited spectrum of activity, patient toxicity, and the emergence of fungal isolates with genetically encoded resistance. A larger concern is the modest efficacy of all three major classes of antifungal drugs, as this is likely a major driver of the excessively high rates of mortality in patients with IFIs and persistence of mucosal infections.

For unexplained reasons, the majority of treatment failures occur in patients infected by fungal isolates that are seemingly sensitive to the selected antifungal therapy, as determined by in vitro susceptibility testing. For example, approximately one-third of patients with a disseminated Candida infection involving isolates deemed susceptible according to current clinical breakpoints fail to respond to treatment with an azole antifungal.

Several host-related factors have been proposed to explain the discordance between in vitro susceptibility tests and patient outcomes, such as inadequate drug distribution to the site of infection or severity of patient immune dysfunction. However, there is only limited evidence to support these arguments, and many treatment failures remain unexplained.

While drug-drug interactions are a serious concern from the perspective of patient toxicity, the effect of most co-administered medications upon fungal physiology and antifungal susceptibility is largely unknown. Using a simple screen of mainly off-patent medications, we recently found that a staggering 139 of the 1280 compounds examined exhibit antagonistic interactions with fluconazole in at least one medically important Candida species. Our preliminary studies have also revealed that non-antifungal medications can have a profound impact upon fungal physiology and upon the outcome of infection in mice.

The objective of this study is to uncover the full scope of antifungal drug-drug antagonistic interactions and assess their potential clinical impact upon treatment outcomes in patients with IFIs.

In Aim 1, we will conduct a comprehensive and systematic set of screens to identify currently approved medications that antagonize the activity of the most relevant antifungal drugs in four of the most prevalent human fungal pathogens. Those acting at pharmacologically relevant concentrations will then be selected, and the extent to which antifungal activity is diminished compared.

Aim 2 will focus upon defining the molecular mechanisms by which antifungal antagonists act and examine their effects upon fungal physiology.

Finally, in Aim 3, we will use a mouse model of invasive candidiasis and conduct a retrospective analysis of patient outcomes to determine if coadministration of antagonistic drugs is sufficient to influence the clinical efficacy of antifungal therapy.

The long-term goal is to improve patient outcomes through establishing integrated treatment protocols that minimize clinically relevant antagonistic drug interactions and therefore maximize antifungal efficacy.

University Of Tennessee

TO ASSIST PUBLIC AND PRIVATE NONPROFIT INSTITUTIONS AND INDIVIDUALS TO ESTABLISH, EXPAND AND IMPROVE BIOMEDICAL RESEARCH AND RESEARCH TRAINING IN INFECTIOUS DISEASES AND RELATED AREAS, TO CONDUCT DEVELOPMENTAL RESEARCH, TO PRODUCE AND TEST RESEARCH MATERIALS. TO ASSIST PUBLIC, PRIVATE AND COMMERCIAL INSTITUTIONS TO CONDUCT DEVELOPMENTAL RESEARCH, TO PRODUCE AND TEST RESEARCH MATERIALS, TO PROVIDE RESEARCH SERVICES AS REQUIRED BY THE AGENCY FOR PROGRAMS IN INFECTIOUS DISEASES, AND CONTROLLING DISEASE CAUSED BY INFECTIOUS OR PARASITIC AGENTS, ALLERGIC AND IMMUNOLOGIC DISEASES AND RELATED AREAS. PROJECTS RANGE FROM STUDIES OF MICROBIAL PHYSIOLOGY AND ANTIGENIC STRUCTURE TO COLLABORATIVE TRIALS OF EXPERIMENTAL DRUGS AND VACCINES, MECHANISMS OF RESISTANCE TO ANTIBIOTICS AS WELL AS RESEARCH DEALING WITH EPIDEMIOLOGICAL OBSERVATIONS IN HOSPITALIZED PATIENTS OR COMMUNITY POPULATIONS AND PROGRESS IN ALLERGIC AND IMMUNOLOGIC DISEASES. BECAUSE OF THIS DUAL FOCUS, THE PROGRAM ENCOMPASSES BOTH BASIC RESEARCH AND CLINICAL RESEARCH. SMALL BUSINESS INNOVATION RESEARCH (SBIR) PROGRAM EXPANDS AND IMPROVES PRIVATE SECTOR PARTICIPATION IN BIOMEDICAL RESEARCH. THE SBIR PROGRAM INTENDS TO INCREASE AND FACILITATE PRIVATE SECTOR COMMERCIALIZATION OF INNOVATIONS DERIVED FROM FEDERAL RESEARCH AND DEVELOPMENT, TO INCREASE SMALL BUSINESS PARTICIPATION IN FEDERAL RESEARCH AND DEVELOPMENT, AND TO FOSTER AND ENCOURAGE PARTICIPATION OF SOCIALLY AND ECONOMICALLY DISADVANTAGED SMALL BUSINESS CONCERNS AND WOMEN-OWNED SMALL BUSINESS CONCERNS IN TECHNOLOGICAL INNOVATION. THE SMALL BUSINESS TECHNOLOGY TRANSFER (STTR) PROGRAM STIMULATES AND FOSTERS SCIENTIFIC AND TECHNOLOGICAL INNOVATION THROUGH COOPERATIVE RESEARCH AND DEVELOPMENT CARRIED OUT BETWEEN SMALL BUSINESS CONCERNS AND RESEARCH INSTITUTIONS, TO FOSTER TECHNOLOGY TRANSFER BETWEEN SMALL BUSINESS CONCERNS AND RESEARCH INSTITUTIONS, TO INCREASE PRIVATE SECTOR COMMERCIALIZATION OF INNOVATIONS DERIVED FROM FEDERAL RESEARCH AND DEVELOPMENT, AND TO FOSTER AND ENCOURAGE PARTICIPATION OF SOCIALLY AND ECONOMICALLY DISADVANTAGED SMALL BUSINESS CONCERNS AND WOMEN-OWNED SMALL BUSINESS CONCERNS IN TECHNOLOGICAL INNOVATION. RESEARCH CAREER DEVELOPMENT AWARDS SUPPORT THE DEVELOPMENT OF SCIENTISTS DURING THE FORMATIVE STAGES OF THEIR CAREERS. INDIVIDUAL NATIONAL RESEARCH SERVICE AWARDS (NRSAS) ARE MADE DIRECTLY TO APPROVE APPLICANTS FOR RESEARCH TRAINING IN SPECIFIED BIOMEDICAL SHORTAGE AREAS. IN ADDITION, INSTITUTIONAL NATIONAL RESEARCH SERVICE AWARDS ARE MADE TO ENABLE INSTITUTIONS TO SELECT AND MAKE AWARDS TO INDIVIDUALS TO RECEIVE TRAINING UNDER THE AEGIS OF THEIR INSTITUTIONAL PROGRAM.

93.855 - Allergy and Infectious Diseases Research

National Institute of Allergy and Infectious Diseases (NIAID) [HHS - NIH]

Memphis, Tennessee 381034902 United States

Single Zip Code

NIH Research Project Grant (Parent R01 Clinical Trial Not Allowed) (PA-20-185)

Amendment Since initial award the total obligations have increased 395% from $618,355 to $3,062,575.