NOVEL CYCLIC BORONATE CELL WALL INHIBITORS TARGETING CARBAPENEM-RESISTANT ACINETOBACTER BAUMANNII - PROJECT…

Assistance award details

Assistance award identifier

ASST_NON_R44AI181353_075

FAIN

R44AI181353

Recipient

VENATORX PHARMACEUTICALS INC

Awarding agency

Department of Health and Human Services

Funding agency

Department of Health and Human Services

Assistance listing (CFDA)

93.855

Total obligated

$3,000,000

Period

Apr 1, 2024 – Mar 31, 2027

Fiscal year

2024

Place of performance state

PA

Source file

FY2024_All_Assistance_Full_20261006.zip

Description

NOVEL CYCLIC BORONATE CELL WALL INHIBITORS TARGETING CARBAPENEM-RESISTANT ACINETOBACTER BAUMANNII - PROJECT SUMMARY Β-LACTAMS INCLUDING CARBAPENEMS ARE THE MOST WIDELY USED ANTIBIOTIC CLASS. CARBAPENEM-RESISTANT A. BAUMANNII (CRAB) REPRESENTS THE MOST EXTREME RESISTANT HUMAN PATHOGEN AMONG THE ACINETOBACTER SPECIES, WHERE ACQUISITION AND EVOLUTION OF Β-LACTAMASES HAVE ESSENTIALLY ELIMINATED ALL THERAPEUTIC OPTIONS. CRAB INFECTIONS ARE 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”. TO PROVIDE A NEW THERAPEUTIC OPTION AGAINST THIS PROMINENT PATHOGEN, VENATORX HAS IDENTIFIED A NOVEL CHEMICAL SERIES OF HIGHLY SELECTIVE CYCLIC BORONATES THAT INHIBIT PENICILLIN-BINDING PROTEINS (PBPS) LIKE Β-LACTAMS BUT THAT ARE IMPERVIOUS TO THE ACTION OF ALL Β-LACTAMASES. THIS RESEARCH PROGRAM AIMS TO DELIVER A CYCLIC BORONATE PBP INHIBITOR (BORO-PBPI) FOR THE TREATMENT OF CRAB INFECTIONS THAT EXPLOITS PORIN MEDIATED UPTAKE RATHER THAN SIDEROPHORE CONJUGATION, IN ORDER TO AVOID BOTH INACTIVATION BY Β-LACTAMASES AND REDUCED ACTIVITY THROUGH LOSS OF SIDEROPHORE UPTAKE AS HAS BEEN OBSERVED WITH CEFIDEROCOL (FETROJA®). SIGNIFICANT STRIDES IN MICROBIOLOGICAL ACTIVITY HAVE BEEN ACHIEVED WITH THE LEAD BORO-PBPI VNRX-14791 EXHIBITING AN MIC90 OF 16 ΜG/ML RELATIVE TO 128/64 ΜG/ML FOR AMPICILLIN-SULBACTAM AND 64/4 ΜG/ML FOR SULBACTAM-DURLOBACTAM AGAINST 26 CRAB CLINICAL ISOLATES. PROTOTYPE BORO-PBPI VNRX-6884 WAS BACTERICIDAL IN VITRO AND ACHIEVED PROOF OF CONCEPT EFFICACY IN THE MURINE THIGH INFECTION MODEL IN CARBAPENEM-PRODUCING A. BAUMANNII WHILE POSSESSING FAVORABLE SELECTIVITY, ADME AND PK PROPERTIES. OPTIMIZATION EFFORTS PROPOSED HEREIN TARGET A 4-FOLD IMPROVEMENT IN ANTIBACTERIAL ACTIVITY TO REACH AN MIC90 ≤4 ΜG/ML, DRIVEN BY RATIONAL STRUCTURE-GUIDED DESIGN FOR ABPBP3 AFFINITY AS WELL AS USING SPECIFIC PHYSICOCHEMICAL PROPERTIES TO IMPROVE CELLULAR ACCUMULATI