R01AI160269

Novel Cyclic Boronate Penicillin Binding Protein Inhibitors to Eliminate the Threat Posed by β-Lactamases and Enable a Future Treatment Option for Carbapenem-Resistant Enterobacterales Infections - Project Summary

Carbapenem-resistance in Enterobacterales has steadily increased over the past decade, leading to multidrug and pan-drug resistance (MDR/PDR), further emphasizing the need for new innovative therapies.

Carbapenem-resistant Enterobacterales (CRE) is a serious global health problem classified by the US Centers for Disease Control and Prevention as an "urgent threat" and by the World Health Organization as a "priority 1 critical threat".

The β-lactams have long been the front-line therapeutic option for such infections, but efficacy of these agents, including last resort carbapenems, is threatened by recent expansion of β-lactamases, particularly subtypes (e.g., NDM) spreading rapidly among Enterobacterales that are unaffected by clinically-available β-lactam/β-lactamase inhibitor combinations.

To address the medical need, Venatorx has identified a novel series of highly selective cyclic boronates that bind to and disrupt penicillin-binding protein (PBP) transpeptidase (TPase) function while avoiding the action of all current and future β-lactamases. This approach creates the first prospect and "rare" new class gram-negative agent to treat infections caused by any β-lactamase-producing CRE pathogen.

Significant strides in microbiological activity have already been achieved within the series by the lead compound VNRX-6736, with an MIC90 of 32 μg/mL relative to 128 μg/mL for meropenem-vaborbactam and ≥1,024 μg/mL for ceftazidime-avibactam in a recent challenge set of 100 CRE isolates. Not only does VNRX-6736 outperform these clinical comparators from an MIC90 perspective, but it does so with a narrow range of MIC owing to β-lactamase avoidance, a feature that will ultimately benefit setting of breakpoints.

The series is rapidly bactericidal, exhibits a low spontaneous mutational frequency (frequency of resistance at 4x MIC of <2.7 x 10-11 in E. coli ATCC 25922), and has favorable ADME and PK properties.

Proof of concept efficacy has been achieved by VNRX-6736 in the murine thigh model of carbapenem-resistant E. coli infection, and pharmacokinetics modeling suggests that 30-45% time above MIC is required to achieve efficacy.

Optimization efforts proposed herein are targeting an 8-fold improvement in antibacterial activity driven by rational structure-guided design to improve PBP binding interaction kinetics to enable an MIC90 = 4 μg/mL. Such an optimized cyclic boronate PBPI could be a first new class antibiotic addressing resistance to β-lactams for the treatment of infections caused by CRE and a long-term therapeutic solution to resistance development in Enterobacterales.

Venatorx Pharmaceuticals

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]

Malvern, Pennsylvania 193551200 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 311% from $1,538,727 to $6,328,779.