Structure-based inhibitor design for reshaping bacterial morphology.

Area of Science:

• Microbiology
• Infectious Diseases
• Drug Discovery

Background:

• The spiral shape of Campylobacter jejuni is crucial for invading intestinal epithelial cells.
• Targeting this morphology could offer new infection prevention strategies.

Purpose of the Study:

• To design and synthesize hydroxamate-based inhibitors targeting Pgp3.
• To investigate the effect of Pgp3 inhibition on C. jejuni morphology and invasion.

Main Methods:

• Chemical synthesis of hydroxamate-based Pgp3 inhibitors.
• Treatment of C. jejuni with inhibitors and observation of morphological changes.
• Crystal structure determination of Pgp3-inhibitor complexes.
• Kinetic and molecular dynamics simulations.

Main Results:

• Inhibitors successfully targeted Pgp3, inducing a morphological shift from helical to rod shape in C. jejuni.
• This change was comparable to pgp3-deletion mutants.
• Structural and simulation data elucidated inhibitor binding modes in the Pgp3 active site.
• Morphological alteration reduced bacterial invasion capability.

Conclusions:

• Pharmacological inhibition of Pgp3 effectively alters C. jejuni morphology.
• Altering bacterial shape is a viable strategy to reduce host cell invasion.
• This study presents a proof of concept for morphology-based anti-infective approaches.