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Nanomechanics of Drug-target Interactions and Antibacterial Resistance Detection
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Ca2+-Daptomycin targets cell wall biosynthesis by forming a tripartite complex with undecaprenyl-coupled

Fabian Grein1,2, Anna Müller1, Katharina M Scherer3

  • 1Institute for Pharmaceutical Microbiology, University Hospital Bonn, University of Bonn, Bonn, Germany.

Nature Communications
|March 21, 2020
PubMed

Insights

Daptomycin, an antibiotic for severe infections, targets bacterial cell wall precursors. This interaction disrupts cell wall synthesis and causes membrane rearrangements, clarifying its mechanism of action against pathogens like MRSA.

Area of Science:

  • Microbiology
  • Molecular Biology
  • Biochemistry

Background:

  • Daptomycin is a crucial antibiotic for treating infections caused by Gram-positive bacteria, including methicillin-resistant Staphylococcus aureus (MRSA).
  • The precise molecular mechanism of daptomycin's action and its specific target have remained elusive.
  • Understanding daptomycin's target is vital for combating antibiotic resistance.

Purpose of the Study:

  • To elucidate the molecular target and mechanism of action of the antibiotic daptomycin.
  • To identify the specific interactions of daptomycin within bacterial cells.
  • To provide a comprehensive model for daptomycin's antibacterial activity.

Main Methods:

  • Utilized microbiological and biochemical assays.
  • Employed fluorescence and optical sectioning microscopy on intact staphylococcal cells.
  • Investigated interactions using model membrane systems.

Main Results:

  • Identified a tripartite complex formed by Ca2+-daptomycin, undecaprenyl-coupled cell envelope precursors, and phosphatidylglycerol.
  • Demonstrated that daptomycin binding primarily occurs at the bacterial septum.
  • Observed interruption of cell wall biosynthesis, delocalization of peptidoglycan machinery, and significant membrane rearrangements.

Conclusions:

  • Daptomycin specifically targets carrier-bound cell wall precursors, explaining its selective toxicity to bacteria.
  • The findings reconcile previous disparate results and support a refined model for daptomycin's mode of action.
  • This research clarifies how daptomycin combats severe Gram-positive bacterial infections.

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