Mapping the metalloregulator repertoire of bacterial pathogens: an integrative genome-mining approach

This work maps the repertoires of bacterial metalloregulators—transcription factors that sense specific metal ions through dedicated coordination sites to control metal uptake and efflux. Combining sequence similarity networks, structural comparisons and SDPs analysis across twelve families, it resolves their functional diversity and the conserved ligand sets and coordination geometries that underlie metal recognition and selectivity, from cysteine-rich to His/carboxylate sites. Cluster-derived HMM profiles then mine four bacterial pathogen genomes, including under-characterized non-model genomes, uncovering lineage-specific expansions. Because sequence homology alone cannot resolve the coordinated metal, specificity is approximated by combining genomic context with coevolution-based prediction of metal-binding residues: about 25% of candidates carried a predicted coordination site, with a markedly non-uniform distribution across metals. By linking coordination chemistry to metal-sensing repertoires in poorly studied pathogens and identify candidate antimicrobial targets.