Membrane-targeting AM-0016 kills mycobacterial persisters and shows low propensity for resistance development

Area of Science:

• Microbiology
• Drug Discovery
• Molecular Biology

Background:

• Persister cells in Mycobacterium tuberculosis pose a significant challenge due to their tolerance to antibiotics.
• Developing strategies to eliminate persister cells is crucial for effective tuberculosis treatment and preventing resistance.
• Targeting bacterial membranes offers a potential avenue for novel antibacterial therapies.

Purpose of the Study:

• To evaluate the efficacy of AM-0016, a novel xanthone-based antibacterial, against growing and persister Mycobacterium tuberculosis.
• To determine the potential of AM-0016 in preventing the emergence of drug resistance.
• To investigate the mechanism of action of AM-0016 on mycobacterial cell membranes.

Main Methods:

• In vitro assessment of AM-0016 activity against actively growing and persister tubercle bacilli.
• Determination of spontaneous resistance mutation frequencies.
• Biochemical analysis of membrane potential and electron microscopy for cell envelope integrity.

Main Results:

• AM-0016 demonstrated rapid sterilization of growing tubercle bacilli and potent bactericidal activity against persister cells.
• The frequency of spontaneous resistance mutations to AM-0016 was found to be very low (less than 10^-8).
• Exposure to AM-0016 led to a rapid collapse of the membrane potential and deformation of the cell envelope.

Conclusions:

• Targeting the cytoplasmic membrane is a promising strategy for eradicating persister mycobacteria.
• This approach holds potential for slowing the development of genetic drug resistance in tuberculosis.
• AM-0016 represents a potential new therapeutic agent for combating drug-tolerant Mycobacterium tuberculosis infections.