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Rapid One-step Enzymatic Synthesis and All-aqueous Purification of Trehalose Analogues
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Rapid One-step Enzymatic Synthesis and All-aqueous Purification of Trehalose Analogues

Published on: February 17, 2017

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Therapeutically useful mycobacteriophages BPs and Muddy require trehalose polyphleates

Katherine S Wetzel1, Morgane Illouz2, Lawrence Abad1

  • 1Department of Biological Sciences, University of Pittsburgh, Pittsburgh, PA, USA.

Nature Microbiology
|August 29, 2023
PubMed

Insights

Mycobacteriophages, used to treat non-tuberculous mycobacterial infections, require specific cell surface glycolipids for infection. Modifying these phages can overcome resistance mechanisms, improving therapeutic potential.

Area of Science:

  • Microbiology
  • Virology
  • Biochemistry

Background:

  • Mycobacteriophages are promising therapeutics for non-tuberculous mycobacterial infections.
  • Understanding phage-host interactions and resistance mechanisms is crucial for clinical application.

Purpose of the Study:

  • To investigate the role of trehalose polyphleates (TPPs) in mycobacteriophage infection and resistance.
  • To identify mechanisms of phage resistance in Mycobacterium abscessus and Mycobacterium smegmatis.
  • To engineer TPP-independent phages for enhanced therapeutic efficacy.

Main Methods:

  • Investigated phage adsorption and infection using TPP-deficient mycobacterial mutants.
  • Employed transposon mutagenesis to identify genes involved in phage resistance.
  • Characterized phage resistance mechanisms through genetic and protein analysis.
  • Engineered clinically relevant phages (BPs and Muddy) for TPP independence.

Main Results:

  • Trehalose polyphleates (TPPs) are essential for infection by phages BPs and Muddy.
  • Loss of TPPs confers resistance to these phages by disrupting adsorption and infection.
  • TPP synthesis gene mutations are a primary cause of phage resistance in clinical isolates.
  • Single amino acid substitutions in phage tail spike proteins render BPs and Muddy TPP-independent.
  • Additional resistance mechanisms exist in TPP-independent phage-resistant mutants.

Conclusions:

  • TPPs are critical determinants of mycobacteriophage infectivity and host range.
  • Phage resistance in mycobacteria frequently involves TPP loss.
  • Engineered TPP-independent phages can overcome TPP-mediated resistance.
  • Clinical deployment of TPP-independent phage mutants may prevent resistance development.

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