COMBATTING MULTIDRUG RESISTANT ACINETOBACTER BAUMANNII WITH CHEMICAL SYNTHETIC LETHALITY - PROJECT SUMMARY…

Assistance award details

Assistance award identifier

ASST_NON_F31AI202953_075

FAIN

F31AI202953

Recipient

THE TRUSTEES OF PRINCETON UNIVERSITY

Awarding agency

Department of Health and Human Services

Funding agency

Department of Health and Human Services

Assistance listing (CFDA)

93.855

Total obligated

$34,114

Period

Aug 1, 2026 – Jul 31, 2029

Fiscal year

2026

Place of performance state

NJ

Source file

FY2026_All_Assistance_Full_20261006.zip

Description

COMBATTING MULTIDRUG RESISTANT ACINETOBACTER BAUMANNII WITH CHEMICAL SYNTHETIC LETHALITY - PROJECT SUMMARY ANTIMICROBIAL RESISTANCE (AMR) IS A MAJOR GLOBAL HEALTH CONCERN: IN 2021, OVER 4.7 MILLION DEATHS WERE ASSOCIATED WITH AMR INFECTIONS. THE MISUSE AND OVERUSE OF ANTIBIOTICS HAVE DRIVEN THE RAPID SPREAD OF RESISTANCE, ESPECIALLY IN GRAM-NEGATIVE BACTERIA, WHILE POOR ECONOMIC INCENTIVES AND DECLINING DISCOVERY EFFORTS HAVE LIMITED THE DEVELOPMENT OF NEW ANTIBIOTICS. THERE IS AN URGENT NEED FOR ALTERNATIVE APPROACHES TO COMBAT THESE INFECTIOUS AGENTS. ONE EMERGING STRATEGY IS CHEMICAL SYNTHETIC LETHALITY, WHEREIN TWO CHEMICALS ARE DEADLY IN COMBINATION BUT INNOCUOUS IN ISOLATION. UNLIKE TRADITIONAL MONOTHERAPY, THE TWO-COMPOUND APPROACH OFFERS GREATER PATHOGEN SPECIFICITY AND REDUCES THE LIKELIHOOD OF SIMULTANEOUS RESISTANCE MUTATIONS. THE GOAL OF THIS PROPOSAL IS TO APPLY CHEMICAL SYNTHETIC LETHALITY TO ACINETOBACTER BAUMANNII, DEVELOP NOVEL DRUG COMBINATIONS, AND LEARN ABOUT THE MOLECULAR AND METABOLIC IDIOSYNCRASIES OF THIS DEADLY PATHOGEN. A. BAUMANNII IS A GRAM-NEGATIVE BACTERIUM THAT HAS BECOME A SIGNIFICANT SOURCE OF HOSPITAL-ACQUIRED INFECTIONS AS IT CAN COLONIZE BOTH EXTERNAL AND INTERNAL SITES IN THE HUMAN BODY. IT IS A CAUSATIVE AGENT OF PNEUMONIA AND CAN INFECT THE SKIN, URINARY TRACT, RESPIRATORY SYSTEM, AND BLOODSTREAM. ITS RESISTANCE TO COMMONLY USED, BROAD-SPECTRUM ANTIBIOTICS, SUCH AS AMINOGLYCOSIDES, Β-LACTAMS, AND CARBAPENEMS, COUPLED WITH ITS OCCURRENCE IN HOSPITAL SETTINGS, MAKES A. BAUMANNII AN IDEAL PATHOGEN FOR APPLYING CHEMICAL SYNTHETIC LETHALITY APPROACHES. THE PROPOSED STRATEGY WILL LEVERAGE A LOW-DOSE ANTIBIOTIC WHICH DOES NOT AFFECT GROWTH BUT GENERATES METABOLIC OR MOLECULAR DEPENDENCIES THAT ARE THEN TARGETED WITH A SECOND MOLECULE. AS PART OF AIM 1, I WILL CONDUCT A HIGH-THROUGHPUT SCREEN OF AN FDA-APPROVED DRUG LIBRARY, TESTING THE GROWTH-INHIBITORY EFFECTS OF THE LIBRARY MEMBERS ALONE AND IN COMBINATION WITH ONE OF THREE CLINIC