Devika Mukherjee1, Hanxun Zou2, Shouping Liu2,3, Roger Beuerman2,3,4, Thomas Dick1. 1. Department of Microbiology & Immunology, Yong Loo Lin School of Medicine, National University of Singapore, 5 Science Drive 2, Singapore 117545. 2. Singapore Eye Research Institute, The Academia, 20 College Road, Discovery Tower Level 6, Singapore 169856. 3. SRP Neuroscience & Behavioural Disorders, Duke-NUS Graduate Medical School, Singapore 169857. 4. Department of Ophthalmology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore 119074.
Abstract
AIM: To test the hypothesis that targeting the cytoplasmic membrane may be an effective way to kill persister mycobacteria and delay the emergence of resistance. METHODS: In vitro activity of AM-0016, a novel xanthone-based antibacterial, was assessed against growing and persister tubercle bacilli. Resistance mutation frequencies were determined. Biochemical membrane and electron microscopic analyses were carried out. RESULTS: AM-0016 rapidly sterilized growing tubercle bacillus cultures and displayed strong bactericidal activity against persister bacteria. Spontaneous resistance mutation frequency was lower than 10(-8). Exposure to AM-0016 resulted in rapid collapse of the membrane potential. Imaging revealed deformation of the cell envelope. CONCLUSION: Targeting the cytoplasmic membrane may be an attractive approach to eliminate persister mycobacteria and slow down the emergence of genetic drug resistance.
AIM: To test the hypothesis that targeting the cytoplasmic membrane may be an effective way to kill persister mycobacteria and delay the emergence of resistance. METHODS: In vitro activity of AM-0016, a novel xanthone-based antibacterial, was assessed against growing and persister tubercle bacilli. Resistance mutation frequencies were determined. Biochemical membrane and electron microscopic analyses were carried out. RESULTS:AM-0016 rapidly sterilized growing tubercle bacillus cultures and displayed strong bactericidal activity against persister bacteria. Spontaneous resistance mutation frequency was lower than 10(-8). Exposure to AM-0016 resulted in rapid collapse of the membrane potential. Imaging revealed deformation of the cell envelope. CONCLUSION: Targeting the cytoplasmic membrane may be an attractive approach to eliminate persister mycobacteria and slow down the emergence of genetic drug resistance.
Entities:
Keywords:
drug resistance; drug tolerance; tuberculosis
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