A bioluminescence-based chemical screen identifies a bactericidal naphthalen-1-ylmethanamine scaffold targeting MmpL3 in Mycobacterium abscessus
Year: 2026
Type: article
Abstract: Treatment of Mycobacterium abscessus pulmonary disease (Mabs-PD) is a growing global health challenge. The lack of bactericidal antibiotics effective at therapeutically relevant concentrations underscores an urgent need for drug discovery. Targeting cell wall synthesis is a promising strategy for drug discovery, as exemplified by the clinical success of broad-spectrum β-lactam antibiotics. Here, we employ a bioluminescence-based whole-cell assay optimized to identify compounds that disrupt both cell wall synthesis and oxidative phosphorylation. A focused drug library screen against Mabs reveals a chemically tractable naphthalen-1-ylmethanamine scaffold with potent bactericidal activity. The optimized derivative GM47-1 targets MmpL3, compromises cell wall integrity, induces ATP leakage, and uncouples respiration. Further chemical optimization yields a derivative with nanomolar minimum inhibitory concentration, bactericidal activity against intracellular Mabs, and efficacy in a zebrafish infection model. Together, these findings identify a promising scaffold for therapeutic development and demonstrate the utility of this bioluminescence-based platform for discovering bactericidal agents against Mabs.
Source: Cell Reports
Institutions: Nanyang Technological University, National University of Singapore, Albert Einstein College of Medicine, Centre National de la Recherche Scientifique, Inserm, Université de Montpellier, Institut de Recherche en Infectiologie de Montpellier, Singapore Centre for Environmental Life Sciences Engineering, Agency for Science, Technology and Research, Infectious Diseases Labs, University of Geneva, University of Zurich, Montana State University, University of Oxford
Language: English
Subfield: Epidemiology
Field: Medicine
Domain: Health Sciences
Open Access status: gold
Estimated APC paid: $5,620
Funders: National Science Foundation, M.J. Murdock Charitable Trust, Montana State University, National Research Foundation, Ministry of Health -Singapore, National Research Foundation Singapore, Ministry of Education - Singapore, Fondation pour la Recherche Médicale, Ministry of Education, India, National Institutes of Health, Office of Research and Economic Development, University of Idaho, Office of Research and Economic Development, Louisiana State University, Medical Research Council, National Medical Research Council, National Institute of General Medical Sciences, Division of Graduate Education, Division of Chemistry
Awards: G1226610473, G1236551632, G1603930703, G166526459, G2466586195, G2909499646, G3434531728, G3749790172, G3902111948, G3937592491, G4154331286, G4382542988, G4539748024, G4933603664, G515965682, MRI: Acquisition of a cryoprobe- and autosampler-equipped AVANCE III 500 MHz solution NMR, G6259889237, G6289264468, G6401591588, G6440740331, G6551576117, G6588211090, G6663034490, G735744473, G7633065944, G787716107, MRI: Acquisition of a 400 MHz Nuclear Magnetic Resonance (NMR) Spectrometer, G8306589951, G8642399960, G8682592842
OpenAlex ID: W7155154589