Substrate Recognition by a Colistin Resistance Enzyme from Moraxella catarrhalis

Area of Science:

• Microbiology
• Structural Biology
• Drug Resistance

Background:

• Colistin is a critical antibiotic for treating infections caused by multidrug-resistant Gram-negative bacteria.
• Plasmid-mediated colistin resistance, mediated by phosphoethanolamine (PEtN) transferase genes like mcr, poses a significant public health threat.
• The origins of these resistance genes, such as mcr-1 in Moraxella species, are increasingly being investigated.

Purpose of the Study:

• To elucidate the molecular mechanism and structural basis of colistin resistance conferred by intrinsic PEtN transferases.
• To determine the crystal structure of the catalytic domain of ICR^Mc from Moraxella catarrhalis.
• To identify sequence signatures for predicting colistin-active PEtN transferases.

Main Methods:

• X-ray crystallography was used to determine the structure of the ICR^Mc catalytic domain.
• The structure was analyzed in complex with PEtN to identify key binding and catalytic residues.
• Structure-guided phylogenetic analysis was performed on related enzyme families.

Main Results:

• The crystal structure of the ICR^Mc catalytic domain in complex with PEtN was determined.
• Key residues involved in catalysis and PEtN binding were identified.
• Dimerization of the ICR^Mc catalytic domain was found to be essential for substrate binding.
• Sequence signatures for potentially colistin-active PEtN transferases were defined.

Conclusions:

• The structural insights into ICR^Mc advance the understanding of PEtN transferase mechanisms and colistin resistance.
• Dimerization is a critical feature for substrate binding in this class of enzymes.
• Phylogenetic analysis provides a tool for identifying novel colistin resistance determinants.