R01AI160247

Sialic Acid Analogs Against Multidrug-Resistant Gonorrhea - Abstract

Gonorrhea is a major public health problem globally. About 87 million new cases of gonorrhea occur worldwide annually. In 2018, 583,405 cases were reported in the U.S, an 82.6% increase in disease incidence since the historic low in 2009. Concomitant infection with HIV and gonorrhea can increase rates of HIV transmission 5-fold. Dysbiosis of the vaginal microbiome (i.e., bacterial vaginosis (BV)) increases the risk of gonorrhea and HIV acquisition and transmission. Serious sequelae of gonorrhea in women include infertility, ectopic pregnancy, and chronic pelvic pain.

Neisseria gonorrhoeae (NG) has become resistant to almost every antibiotic in clinical use. Reports of resistance to ceftriaxone and azithromycin from almost every continent portend an era of untreatable gonorrhea. Development of novel therapies against NG is a global public health priority.

Gonococci deploy a unique immune evasion strategy wherein it caps its lipooligosaccharide (LOS) by a surface LOS sialyltransferase (LST) using host-derived CMP-Neu5Ac. LOS sialylation enables NG to evade several aspects of host immunity, including complement and cationic antimicrobial peptides (CAMPs). We discovered that gonococci fed with CMP-nonulosonates (CMP-NULOs), such as CMP-legionaminic acid (CMP-LEG5,7AC2) and CMP-ketodeoxynonulosonate (CMP-KDN), cap their LOS with these NULOs. Incorporation of NULOs into NG LOS renders bacteria susceptible to complement and CAMPs. Importantly, CMP-NULOs significantly shorten the duration and burden of NG vaginal colonization in mice. Cathelicidin (a member of the CAMP family) played a key role in the mechanism of action of CMP-NULOs. Our efficacy, safety, and stability studies have established CMP-LEG5,7AC2 and CMP-KDN as promising candidates for intravaginal delivery to prevent NG acquisition.

In years 1-2 of Aim 1, the NRC will produce CMP-NULOs for all work in this proposal, perform a pharmacoeconomic analysis, and assess scale-up. Process development, quality release assays, development of potency assays, and stability in simulated genital tract fluids of the identified lead will follow in years 3-5. Aim 2 will elucidate factors that may affect the safety and efficacy of CMP-NULOs. These include effects of CMP-NULOs on growth and viability of favorable or unfavorable vaginal bacteria, the effects of sialidases elaborated by BV-associated pathogens, and naturally-occurring anti-NULO antibodies on the efficacy of CMP-NULOs in vitro and in vivo. Additionally, examining cervicovaginal secretions for CMP-NULO hydrolase activity and testing the specificity of CAMPs to bind NULO-containing glycans will refine the mechanism of action of CMP-NULO against NG. Aim 3 will formulate the CMP-NULOs into intravaginal rings (IVRs), perform PK studies in vitro and in a sheep model, and examine biofilm formation by vaginal microbiota on IVRs. Work in years 1-2 of Aims 1-3 will identify a single lead; work in years 3-5 will focus on further product development and IND-enabling activities. Aim 4 will verify the activity of the lead CMP-NULO against genetically and geographically diverse NG isolates. Aim 5 includes regulatory guidance and oversight for all aims that will culminate in a pre-IND meeting with the FDA.

University Of Massachusetts Medical School

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]

Worcester, Massachusetts 01655 United States

Single Zip Code

Partnerships for Countermeasures against Select Pathogens (R01 Clinical Trials Not Allowed) (RFA-AI-20-028)

Amendment Since initial award the total obligations have increased 287% from $1,316,757 to $5,099,184.