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BackgroundCarbapenem-resistant Klebsiella pneumoniae (CRKP) remains a major clinical pathogen and public health threat with few therapeutic options. The mobilome, resistome, methylome, virulome and phylogeography of CRKP were characterised.MethodsCRKP collected in 2018 were subjected to antimicrobial susceptibility testing, screening by multiplex-PCR, genotyping by Repetitive Element Palindromic-Polymerase Chain Reaction (REP-PCR), plasmid size, number, incompatibility, and mobility analyses, and PacBio’s SMRT sequencing (n=6).Results & conclusionThere were 56 multidrug-resistant CRKP, having blaOXA-48-like and blaNDM-1/7 carbapenemases on self-transmissible IncF, A/C, IncL/M and IncX3 plasmids endowed with prophages, traT, resistance islands and type I and II restriction modification systems (RMS). These plasmids were of close evolutionary relationship to several plasmids globally whilst the strains also clustered with several global clades, evincing transboundary horizontal and vertical dissemination. Reduced susceptibility to colistin occurred in 23 strains. Common clones included ST307, ST607, ST17, ST39, and ST3559. IncFIIk virulent plasmid replicon was present in 56 strains. The six strains contained at least 41 virulence genes and four different K- and O-loci types: KL2, KL25, KL27, KL102, O1, O2, O4 and O5. Types I, II, and III RMS, conferring m6A (GATC, GATGNNNNNNTTG, CAANNNNNNCATC motifs) and m4C (CCWGG) modifications on chromosomes and plasmids, were found.There is plasmid-mediated, clonal, and multiclonal dissemination of blaOXA-48-like and blaNDM-1 in South Africa, mirroring international epidemiology of similar clones and plasmids. Plasmid-mediated transmission of RMS, virulome and prophages influence bacterial evolution, epidemiology, pathogenicity, and resistance, threatening infection treatment. RMS influence on antimicrobial and bacteriophage therapy needs urgent investigation.Highlights/ImportanceK. pneumoniae is a major pathogen implicated in numerous nosocomial infections. Worryingly, we show that K. pneumoniae isolates from South Africa, Africa and globally are endowed with rich resistomes and mobilomes that make them almost pandrug resistant. The isolates in this study contained rich virulomes and prophages on both chromosomes and plasmids, with close evolutionary kith or kin to other plasmids identified worldwide. There was a rich diversity of restriction modification systems that regulate virulence, transcription, and plasmid mobility in bacteria, facilitating the epidemiology, resistance, pathogenicity and genomic evolution of the strains, and threatening antimicrobial and bacteriophage therapy.