Structural insights into the advancements of mobile colistin resistance enzymes

Area of Science:

• Microbiology
• Structural Biology
• Drug Discovery

Background:

• Plasmid-encoded mobile colistin resistance (MCR) enzymes compromise colistin's effectiveness against multidrug-resistant bacteria.
• MCRs function as transferases, adding phosphoethanolamine to lipid A, with the catalytic domain well-studied.
• The roles of soluble or inter-membrane domains in MCRs remain unclear, potentially leading to misunderstandings of substrate binding.

Purpose of the Study:

• To provide a comprehensive analysis of MCR-1, focusing on the full-length structure.
• To address disputed aspects of MCR architecture and catalytic mechanisms.
• To identify potential drug design targets and summarize current MCR-1 inhibitor strategies.

Main Methods:

• Comparative analysis of MCR-1 using full-length Alpha-Fold models.
• Critical evaluation of MCR variants, their evolution, and associated survival costs.
• Review of recent advancements in MCR-1 inhibitor development.

Main Results:

• The full-length MCR-1 structure offers a novel perspective on enzyme architecture and function.
• Re-identification of potential drug design pockets by comparing full-length and catalytic domain structures.
• Insights into the evolutionary dynamics and resistance-survival trade-offs of MCR variants.

Conclusions:

• Understanding the full-length MCR-1 structure is crucial for accurate insights into its function and substrate interactions.
• The identified drug design pockets represent promising avenues for developing new MCR-1 inhibitors.
• This review provides a foundation for future drug development against colistin-resistant bacteria.