Research in the Aragaw Lab
Mycobacterium abscessus (Mab) is a rapidly growing pathogen and a leading cause of chronic, pulmonary disease particularly in patients with cystic fibrosis, bronchiectasis, or other structural lung conditions. Treatment of Mab lung disease is notoriously difficult with no reliable cure: the bacterium is intrinsically resistant to a wide spectrum of antibiotic classes, and the discovery and development pipeline remains thin. There is an urgent medical need for new, more potent anti-Mab agents. Dr. Aragaw pursues two complementary drug discovery strategies to address this gap.
De novo target-lead discovery: The first strategy aims to identify novel antimycobacterial target-lead pairs through unbiased, high-throughput screening of collections of chemically diverse small molecules against Mab. As part of this effort, we are conducting a dedicated screen of the Global Health Chemical Diversity Library (GHCDLv2) in collaboration with the Drug Discovery Unit (DDU) at the University of Dundee. Active compounds (“hits”) emerging from these campaigns are advanced into secondary assays to refine potency profiles, followed by target identification using genetic and biochemical approaches. Validated target-lead pairs then form the starting point for medicinal chemistry-driven hit‑to‑lead optimization toward preclinical development candidates, in partnership with our medicinal chemistry collaborators.
The second strategy employs a repositioning approach: chemically re-engineering approved or clinically advanced antibiotic classes with pharmacologically validated targets for enhanced activity against Mab. One current effort focuses on fluoroquinolones, a class designated by the WHO as “highest priority critically important antimicrobials.” They possess attractive pharmacological properties for the treatment of lung infection, including excellent oral bioavailability, extensive tissue penetration, and concentration-dependent bactericidal activity. Despite these advantages, their clinical utility in Mab lung disease is limited by intrinsically poor potency against this pathogen. We are systematically investigating the mechanistic basis for this potency gap and developing optimized fluoroquinolone analogs with enhanced anti-Mab activity, while preserving the PK/PD properties that make this class clinically valuable. This work is conducted in collaboration with Dr. Sudeshna Roy (medicinal chemist) at the University of Tennessee Health Science Center.
Selected Publications
Aragaw WW, Gebresilase TT, Negatu DA, Dartois V, Dick T. Multidrug tolerance conferred by loss-of-function mutations in anti-sigma factor RshA of Mycobacterium abscessus. Antimicrob Agents Chemother. 2024;68:e01051-24.
PMID: 39470195
Aragaw WW, Negatu DA, Bungard CJ, Dartois VA, El Marrouni A, Nickbarg EB, Olsen DB, Warrass R, Dick T. (2024). Pharmacological validation of dihydrofolate reductase as a drug target in Mycobacterium abscessus. Antimicrobial Agents and Chemotherapy 68:e00717-23.
PMID: 38018963
Aragaw WW, Cotroneo N, Stokes S, Pucci M, Critchley I, Gengenbacher M, Dick T. (2022). In vitro resistance against DNA gyrase inhibitor SPR719 (fobrepodacin) in Mycobacterium avium and Mycobacterium abscessus. Microbiology Spectrum 10(1):e01321-21.
PMID: 35019671
Aragaw WW, Lee BM, Yang X, Zimmerman MD, Gengenbacher M, Dartois V, Chui W-K, Jackson CJ, Dick T. (2021). Potency boost of a Mycobacterium tuberculosis dihydrofolate reductase inhibitor by multienzyme F420H2-dependent reduction. PNAS USA 118(25).
PMID: 34161270
Proietto J, Tatek B, Folvar C, Jimenez DC, Alshiraihi IM, Gonzalez-Juarrero M, Saliu F, Vacca F, Cirillo DM, Lore N, Dick T, Dartois V, Aragaw WW. Preparation of agar bead–embedded Mycobacterium abscessus to inoculate immunocompetent mice intratracheally. J Vis Exp. 2025 Apr 25;(218):67602. doi:10.3791/67602.
PMID: 40354234