Emergence of in Extended-Spectrum-β-Lactamase-Producing Clinical in Pretoria, South Africa: Global Evolutionary Phylogenomics, Resistome, and Mobilome.

Extended-spectrum-β-lactamase (ESBL)-producing are critical-priority pathogens that cause substantial fatalities. With the emergence of mobile genes mediating resistance to colistin in , clinicians are now left with few therapeutic options. Eleven clinical strains with resistance to cephems and/or colistin were genomically analyzed to determine their resistomes, mobilomes, and evolutionary relationships to global strains. The global phylogenomics of genes and bearing genomes were further analyzed. Ten isolates were ESBL positive. The isolates were multidrug resistant and phylogenetically related to global clones but distant from local strains. Multiple resistance genes, including , and , were found in single isolates; IS, IS, and Tn transposons bracketed and Common plasmid types included IncF, IncH, and ColRNAI. was of close sequence identity to , and Genomes bearing clustered into six main phyletic groups (A to F), with those of this study belonging to clade B. species and species are the main hosts of globally, although diverse promiscuous plasmids disseminate across different bacterial species. Emergence of in ESBL-producing in South Africa is worrying, due to the restricted therapeutic options. Intensive One Health molecular surveillance might discover other alleles and inform infection management and antibiotic choices. Colistin is currently the last-resort antibiotic for difficult-to-treat bacterial infections. However, colistin resistance genes that can move from bacteria to bacteria have emerged, threatening the safe treatment of many bacterial infections. One of these genes, , has emerged in South Africa in bacteria that are multidrug resistant, further limiting treatment options for clinicians. In this work, we show that this new gene is disseminating worldwide through and species through multiple plasmids. This worrying observation requires urgent action to prevent further escalation of this gene in South Africa and Africa.