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The Mycomembrane Differentially and Heterogeneously Restricts Antibiotic Permeation
Irene Lepori1, Kiserian Jackson1,2, Zichen Liu3,4
1Department of Microbiology, University of Massachusetts, Amherst, Massachusetts 01003, United States.
ACS Infectious Diseases
|June 5, 2025
Summary
The mycobacterial outer membrane selectively blocks antibiotic entry, acting as a cell-specific barrier. This finding, using the Peptidoglycan Accessibility Click-Mediated AssessmeNt (PAC-MAN) method, reveals differential drug permeation in Mycobacterium tuberculosis.
Area of Science:
- Microbiology
- Cell Biology
- Drug Discovery
Background:
- The outer mycomembrane of Mycobacterium tuberculosis is widely considered a primary barrier to antibiotic treatment.
- Previous studies supporting this hypothesis relied on indirect evidence or bulk population measurements.
Purpose of the Study:
- To investigate the role of the mycobacterial mycomembrane as a barrier to antibiotic entry using a novel method.
- To determine if the mycomembrane exhibits differential permeability to various molecules and antibiotics.
Main Methods:
- Utilized the Peptidoglycan Accessibility Click-Mediated AssessmeNt (PAC-MAN) method to trap azide-modified small molecules within the peptidoglycan layer of live mycobacteria.
- Applied PAC-MAN to analyze the differential restriction of fluorophores and antibiotic derivatives by the mycomembrane.
Main Results:
- The mycomembrane was shown to differentially restrict access of fluorophores and antibiotic derivatives in both M. tuberculosis and M. smegmatis.
- Discrimination was observed between different classes of antibiotics and within the fluoroquinolone family.
- Analysis of subpopulations revealed heterogeneous restriction of certain fluorophores and vancomycin by the mycomembrane.
Conclusions:
- The mycobacterial mycomembrane acts as a dynamic, molecule- and cell-specific barrier to antibiotic permeation.
- This finding has significant implications for understanding antibiotic resistance and developing new therapeutic strategies against tuberculosis.
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