Journal Article

Chemoproteomic elucidation of β-lactam drug targets in Mycobacterium abscessus

Devlin, Kaylyn L, Lin, Vivian S, Nelson, William C, Gorham, Leo J, Leach, Damon T, Beatty, Kimberly E, Lamichhane, Gyanu, Hutchinson, Emily

2025

Overview

The pathogen ( ) can cause severe and difficult to treat chronic lung infections. Despite the rising incidence and clinical concern of infections, treatment options are limited and often ineffective. Treatment is complicated by 's ability to persist in a non-replicative, drug-resistant state. Several β-lactam antibiotics are potently bactericidal against but are underutilized because their molecular mechanisms of action against are incompletely understood. In the current study, we used β-lactam-derived activity-based probes and chemoproteomics to report the first comprehensive list of enzymes in targeted by β-lactams. We compared β-lactam targets across two subspecies in actively replicating and non-replicative cultures, using a new carbon starvation model of persistence. We identified 17 targets that were active in every condition tested, seven of which were previously unknown to bind β-lactams. Lastly, we characterized the β-lactamase activity and β-lactam inhibition profiles of nine enzymes, demonstrating that imipenem inhibits these targets more effectively than cefoxitin. These findings provide clarity on the mechanisms of action of clinically relevant β-lactams in , a crucial step toward fully realizing their potential for treating infections caused by this opportunistic pathogen.

• Publisher: Cold Spring Harbor Laboratory Preprints