R01AI173238

Optimizing Multi-Drug Mycobacterium Tuberculosis Therapy for Rapid Sterilization and Resistance Suppression - Project Summary/Abstract

In P01 AI123036, we were able to generate an algorithm that ranked single agents for Mycobacterium tuberculosis (MTB), identified promising 2-drug combinations, and, with a completely novel mathematical approach, identified 3-drug regimens predicted to be significantly better than 2-drug regimens. These predictions were prospectively validated in a BALB/C model (H37RV) and in a non-human primate model of MTB (Erdman strain).

In this proposal, we will extend our previous work. There is a large number of new MTB agents, many with novel mechanisms of action. We have 4 specific aims (SA) that, when complete, will allow us to identify multi-drug combinations that will optimize the rate of kill for organisms in 3 different metabolic states and will suppress resistance emergence.

In the Hollow Fiber Infection Model (HFIM) (SA#1), we will be able to rank new agents based on potency and physicochemical properties. The HFIM provides insight into the drug's exposure-response for kill and resistance suppression. We identified a near optimal 3-drug regimen (PMD/MFX/BDQ). With new single agents, we can examine substituting a new agent for an older agent and we can expand the regimens to identify a near-optimal 4-drug regimen. This will be particularly important for patients with high bacterial burdens.

In SA #2, we will test regimens from SA#1 in two murine models (BALB/C & C3HEB/FEJ mice). These will give somewhat different information. Both give information regarding kill and resistance suppression. Kramnik mice have pathology more closely resembling that in humans. We will use Matrix-Assisted Laser Desorption Ionization-MS Imaging and Laser Capture Microdissection LCMS. This allows identification of spatial distribution and quantification of drugs. A question regarding cure is how long to wait to sacrifice animals to document eradication. Some agents (BDQ) have long tissue half-lives. We will document rates of ingress/egress of drugs into the infection site, allowing determination when animal cohorts may be sacrificed to document eradication.

In SA #3, we will document mechanisms of antimicrobial effect quantitatively. We have generated a first-of-a-kind dynamic model for PBP-binding in MTB and will link this to rates of cell kill. We have also developed AMP/ADP/ATP intracellular assays. These will be employed for agents like diarylquinolines (e.g. BDQ) and PMD that act as energy poisons (for PMD, this occurs under anaerobic/non-replicative conditions). We will measure intracellular (MTB) drug concentrations, linking them to effect alone and in combination therapy experiments. Proposal success rests on modeling of the data.

In SA #4, we have written code to extend earlier analyses, going from 3- to 4-drug regimens. For these high-dimensional models, we developed several approaches to speed up analysis, making them computationally tractable. At proposal end, we shall develop a 4-drug algorithm allowing rapid identification of near optimal regimens that work for both susceptible and less-susceptible organisms. The algorithm will be general. It will work well for today's agents but also for agents as discovered.

University Of Florida

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]

Florida United States

State-Wide

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

Amendment Since initial award the total obligations have increased 208% from $1,314,301 to $4,042,959.