R01AI170889

Development of a Broad Spectrum Teixobactin-Lipopeptide Hybrid for the Treatment of Lung Infections Caused by Pan-Drug Resistant "Superbugs"

Abstract

The goal of this project is to develop a broad-spectrum dry powder inhalation teixobactin-lipopeptide hybrid aimed at preventing and treating lung infections caused by bacterial "superbugs". The successful use of any antibiotic is compromised by the potential development of resistance to that compound from the time it is first used. The world is facing an enormous and growing threat from the emergence of pan-drug resistant (PDR) bacteria that are resistant to all available antibiotics. New antibiotics with novel mechanisms of action and against which bacteria cannot easily develop resistance are urgently needed to treat lung infections caused by the PDR gram-negative pathogens like Pseudomonas aeruginosa, Acinetobacter baumannii, and Klebsiella pneumoniae, as well as gram-positive strains of methicillin-resistant Staphylococcus aureus (MRSA) and Streptococcus pneumoniae.

Teixobactin is a recently discovered new antibiotic that possesses a novel mechanism of action (MOA), albeit a narrow spectrum of activity against gram-positive bacteria. The most notable property of teixobactin is that it is the first and only antibiotic that bacteria cannot easily develop resistance against. We have developed novel teixobactin-lipopeptide hybrids that are superior to native teixobactin as they retain this key anti-resistance property and, in addition, have a broader spectrum with potent activity against PDR gram-negatives, as well as PDR gram-positives.

Our preliminary data show that our teixobactin-lipopeptide hybrids, delivered as a dry powder inhalation, have significantly improved efficacy for the treatment of lung infections by virtue of their unique MOA, no detectable resistance, high local exposure in the lungs with low systemic exposure, and low toxicity. Importantly, the hybrids displayed superior in vivo efficacy compared to treatment with the combination of the individual compounds or each compound per se. This is a significant development in the field as the teixobactin-lipopeptide hybrid represents the first-in-class broad-spectrum "resistance-proof" dry powder inhalation antibiotic for the treatment of PDR bacterial lung infections.

Our internationally recognized track records in antibiotic discovery, pharmacology, anti-infective dry powder formulation, pharmacokinetics/pharmacodynamics, and state-of-the-art facilities for antimicrobial development provide extremely strong support for this project. The proposal will employ a purpose-designed funneling approach to identify a lead candidate (plus one back-up) that is active against PDR gram-negative strains of P. aeruginosa, A. baumannii, and K. pneumoniae, as well as gram-positive strains of MRSA and S. pneumoniae, for preclinical development and IND-enabling studies.

University Of Southern California

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]

Los Angeles, California 90089 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 463% from $676,074 to $3,805,029.