R01AI153264

Development of Novel Anti-Neisseria Gonorrhoeae Therapeutic Agents - Project Abstract:

Gonorrhea is a sexually transmitted disease caused by the bacterial pathogen Neisseria gonorrhoeae that colonizes urogenital, anal, and nasopharyngeal tissues. Locally in the United States, the Centers for Disease Control and Prevention (CDC) reported a 67% increase of gonorrhea cases between 2013 – 2017 with >550,000 cases in 2017 alone.

N. gonorrhoeae wreaks havoc on world health care systems, causing pelvic inflammatory disease, infertility, and ectopic pregnancies. The bacteria can also be transmitted from mother to child during birth and lead to blindness. If left untreated, N. gonorrhoeae can cause gonococcemia resulting in skin infection, arthritis, or endocarditis.

Pathogenic gonorrhea strains are increasingly resistant to common front-line antibiotics. The World Health Organization (WHO) surveillance program reports resistance to most available antibiotics. Rampant resistance has caused the CDC and the WHO each to classify N. gonorrhoeae as a superbug, and a future with an untreatable gonococcal infection is a real possibility.

Thus, there is significant unmet need to identify novel targets and molecules with therapeutic potential. Studies proposed in this application build upon discoveries that FDA-approved carbonic anhydrase inhibitors (CAIs), such as acetazolamide and ethoxzolamide, display potent antimicrobial activity, in an applicable clinical range, against N. gonorrhoeae. CAIs, and analogs we have designed, also have no antimicrobial effect on commensal bacteria, reducing the potential for problematic dysbiosis caused by antibiotic treatment.

We have shown that the molecules exhibit their antibiotic effect by inhibiting the carbonic anhydrase from N. gonorrhoeae and have validated N. gonorrhoeae carbonic anhydrase (NGCA) as a viable anti-gonococcal therapeutic target. Our team has improved the potency of the CAI-based inhibitors from 4 μg/mL to 0.5 μg/mL.

This proposal will continue lead optimization of CAI-based analogs using structure-based design while incorporating modifications to improve permeability into the gram-negative cell. Molecules will be assessed in in vitro antimicrobial assays and prioritized analogs will progress to in vitro pharmacokinetic (PK) and pharmacologic profiling.

Finally, top performing analogs will be assessed for in vivo efficacy in various gonorrhea mouse models, as well as evaluated in safety and pharmacokinetic assays to support future lead selection and investigational new drug enabling studies.

Purdue University

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]

West Lafayette, Indiana 479072091 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 292% from $780,073 to $3,055,792.