Functional genomic mapping of gene vulnerability in mycobacterium abscessus across host-relevant environments

The National Institute of Allergy and Infectious Diseases, within the Department of Health and Human Services, awarded The Rockefeller University $667,659 on June 1, 2026, for functional genomic mapping of gene vulnerability in Mycobacterium abscessus across host-relevant environments under the Allergy and Infectious Diseases Research program (CFDA 93.855).

The award funds genome-scale CRISPR interference screening to systematically quantify gene vulnerability in M. abscessus, an increasingly prevalent cause of chronic lung infections in individuals with cystic fibrosis, bronchiectasis, and other structural lung diseases. Current antibiotic regimens for M. abscessus are prolonged, poorly tolerated, and only modestly effective; M. abscessus shows high intrinsic antibiotic resistance. The work will define gene vulnerabilities across three distinct growth conditions, including a validated synthetic cystic fibrosis sputum medium; validate high-priority condition-specific targets and investigate their mechanisms of action; and perform genome-scale CRISPR interference screening during macrophage infection to identify genes required for intracellular survival. The research will uncover how host-like infection conditions reshape M. abscessus physiology and gene vulnerability, define new therapeutic targets, and establish broadly applicable methods for functional genomic analysis in M. abscessus and other nontuberculous mycobacteria.

Place of performance is New York, New York 10065. The period of performance runs through May 31, 2031.

Abstract

Mycobacterium abscessus (mabs) is an increasingly prevalent cause of chronic lung infections, especially among individuals with cystic fibrosis (CF), bronchiectasis, or other structural lung diseases. Treatment outcomes for mabs are dismal: current regimens are prolonged, poorly tolerated, and only modestly effective. Mabs shows high levels of intrinsic antibiotic resistance, and therapeutic development has lagged far behind progress made for mycobacterium tuberculosis. This project aims to accelerate the discovery of condition- specific vulnerabilities in mabs using genome-scale crispr interference (crispri) to systematically quantify gene vulnerability under physiologically relevant conditions. We have developed and optimized crispri platforms for mabs and constructed the first genome-wide crispri library in this pathogen. Using this platform, we will (1) define gene vulnerabilities across three distinct growth conditions, including a validated synthetic CF sputum medium; (2) validate high-priority condition-specific targets and investigate their mechanisms of action; and (3) perform genome-scale crispri screening during macrophage infection to identify genes required for intracellular survival. Our approach will uncover how host-like infection conditions reshape mabs physiology and gene vulnerability, define new therapeutic targets, and establish broadly applicable methods for functional genomic analysis in mabs and other nontuberculous mycobacteria. Ultimately, this work will lay the foundation for future drug discovery efforts aimed at a pathogen of rising clinical importance.