Structural insights into the advancements of mobile colistin resistance enzymes.

The plasmid-encoded mobile colistin resistance enzyme (MCR) is challenging the clinical efficacy of colistin as a last-resort antibiotic against multidrug-resistant bacteria. This transferase catalyzes the addition of positively charged phosphoethanolamine to lipid A, and its catalytic domain in the periplasm has been elucidated. To date, there are many works on the catalytic domain and function of this enzyme class. However, the roles of unreported soluble or inter-membrane domains remain undefined, which might cause an inaccurate or even incorrect understanding of substrate recognition and binding. In this review, MCR-1 is first compared and analyzed from the perspective of the full-length alpha-fold MCR-1. Specifically, some disputed issues, especially in its architecture and catalytic mechanism are discussed independently. Meanwhile, the structure-based insights into MCRs variants, their evolutions, and the balance between colistin-resistance and survival costs, are also critically analyzed. Importantly, by comparing it with the full-length MCR-1, several potential pockets for drug design have been re-identified. Finally, recent advancements in inhibitors targeting MCR-1 are also in-depth summarized. These details offer a new perspective on MCRs and serve as a valuable foundation for drug development.