Predatory myxobacteria lay at the cross-roads of metallo-β-lactamase evolution

Understanding the biology of B1 metallo-β-lactamases (MβLs) in their native hosts and the molecular bases of the adaptive mechanisms during the transfer process to human pathogens, may provide novel therapeutic insights against these important resistance factors. Through large scale phylogenomic analyses, we identified Bacteroidota and Myxococcota as the primary hosts of the enzymes in environmental habitats. The monophyletic lineage of MβL homologues from the predatory members of the latter phylum shared common ancestry with clinically relevant families found in γ-Proteobacteria, highlighting their evolutionary significance. Resistance phenotypes and biochemical properties of native MβLs from three myxobacterial genera expressed in the model γ-proteobacterium, Escherichia coli, and comparisons with the New Delhi Metallo-β-lactamase revealed that evolution of the enzymes concerned mainly adaptations enhancing their production in the new hosts rather than functional differentiation. Periplasmic localization is the main evolved trait, with E. coli not recognizing optimally the signal peptides of the environmental MβLs which were secreted as soluble proteins in the cell envelope despite predicted to be lipoproteins. The unique features of N-terminal secretory signals of myxobacterial MβLs likely reflected the enzymes integration into the physiology of their hosts and pointed to naturally occurring molecules potentially controlling their expression.