Predatory Myxobacteria are Ancestral Hosts of Clinically Relevant Metallo-β-Lactamases (MβLs)
Background
The escalating crisis of antimicrobial resistance (AMR) necessitates a deeper understanding of resistance mechanisms like metallo-β-lactamases (MβLs). These enzymes degrade β-lactam antibiotics, rendering many crucial drugs ineffective. While novel β-lactam/β-lactamase inhibitors offer some hope, MβLs remain a significant challenge due to their rapid spread and diverse origins. Understanding the native hosts and evolutionary pathways of MβLs is critical for developing new therapeutic strategies and predicting future resistance trends.
Study Design
Researchers conducted large scale phylogenomic analyses to identify primary environmental hosts of B1 MβLs. They focused on MβL homologues from predatory myxobacteria, comparing their evolutionary lineage to clinically relevant families in γ-Proteobacteria. To characterize functional aspects, native MβLs from three myxobacterial genera were expressed in the model γ-proteobacterium, Escherichia coli. Resistance phenotypes and biochemical properties were then assessed and compared against the well-known New Delhi Metallo-β-lactamase (NDM-1) to understand adaptive mechanisms.
Results
Phylogenomic analyses identified Bacteroidota and Myxococcota as the primary environmental hosts for MβLs. A monophyletic lineage of MβL homologues from predatory myxobacteria was found to share common ancestry with clinically relevant MβL families in γ-Proteobacteria, underscoring their evolutionary significance. The study revealed that the evolution of these enzymes primarily involved adaptations enhancing their production in new hosts, rather than significant functional differentiation. Specifically, periplasmic localization emerged as a key evolved trait. > E. coli did not optimally recognize the signal peptides of environmental MβLs, which were secreted as soluble proteins in the cell envelope despite being predicted as lipoproteins. This suggests unique N-terminal secretory signals of myxobacterial MβLs, likely reflecting their integration into host physiology and pointing to naturally occurring molecules that could control their expression.
Key Findings
- Bacteroidota and Myxococcota are identified as primary environmental hosts for B1 metallo-β-lactamases (MβLs).
- Myxobacterial MβL homologues share common ancestry with clinically relevant MβLs found in γ-Proteobacteria.
- MβL evolution primarily involved adaptations enhancing enzyme production in new hosts, not functional differentiation.
- Periplasmic localization is a main evolved trait for MβLs in new bacterial hosts like
E. coli. - Unique N-terminal secretory signals of myxobacterial MβLs suggest host-specific integration and potential control mechanisms.
Why It Matters
Understanding the evolutionary origins of MβLs in environmental bacteria like myxobacteria provides crucial insights into the global spread of antimicrobial resistance. This knowledge can inform strategies to predict and potentially prevent the emergence of new resistance factors in clinical settings. By identifying the specific adaptations that facilitate MβL transfer and expression in pathogens (e.g., enhanced production, periplasmic localization), new therapeutic targets could be developed. For instance, targeting the unique secretory signals or the mechanisms enhancing MβL production in new hosts could offer novel avenues for β-lactamase inhibitors, moving beyond direct enzyme inhibition to disrupt the resistance pathway itself. This research highlights that the challenge isn't just about blocking the enzyme, but also understanding and interfering with its successful integration into pathogenic bacteria.
metallo-beta-lactamase
antimicrobial-resistance
bacterial-evolution
myxobacteria
escherichia-coli
phylogenomics