Journal
FUTURE MICROBIOLOGY
Volume 11, Issue 5, Pages 643-650Publisher
FUTURE MEDICINE LTD
DOI: 10.2217/fmb-2015-0015
Keywords
drug resistance; drug tolerance; tuberculosis
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Funding
- Singapore Ministry of Health's National Medical Research Council under its Translational Clinical Research Flagship grant [NMRC/TCR/011-NUHS/2014]
- Singapore Ministry of Health's National Medical Research Council under its Centre grant 'MINE'/Research Core number [4 (NMRC/CG/013/2013), SHF/FG538P/2013-SingHealth Foundation]
- Singapore Programme of Research Investigating New Approaches to Treatment of Tuberculosis (SPRINT-TB) [NMRC/TCR/R1018]
- Yong Loo Lin School of Medicine
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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.
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