Multi-Omics Characterisation of Antimicrobial Resistance Mechanisms in Hospital-Acquired Klebsiella pneumoniae Isolates from Tertiary Hospitals in the North West Geopolitical Zone

Hospital-acquired infections caused by carbapenem-resistant Klebsiella pneumoniae represent a critical threat in Nigerian tertiary hospital settings, where treatment options are severely constrained by limited access to last-resort antibiotics and inadequate infection control infrastructure. Understanding the molecular architecture of resistance at a genomic, transcriptomic, and metabolomic level is essential to identifying novel therapeutic vulnerabilities. This study applied a multi-omics approach to characterise antimicrobial resistance mechanisms in carbapenem-resistant K. pneumoniae isolates recovered from bloodstream infections at teaching hospitals in Kano, Sokoto, and Kaduna States. Whole genome sequencing was performed using Illumina short-read and Oxford Nanopore long-read sequencing platforms. Comparative genomics identified resistance gene carriage, mobile genetic element associations, and virulence gene profiles. Transcriptomics by RNA-seq compared gene expression in carbapenem-susceptible and resistant pairs under sub-inhibitory meropenem exposure. Untargeted metabolomics characterised intracellular metabolite perturbations during carbapenem challenge. Integration of multi-omics data identified novel co-regulatory networks linking outer membrane porin downregulation, KPC-type carbapenemase expression, and metabolic flux redirection as convergent resistance mechanisms. A previously unreported plasmid-mediated integron cassette was identified carrying two novel resistance gene combinations. These original findings advance understanding of carbapenem resistance evolution in Nigerian hospital K. pneumoniae and nominate specific resistance gene nodes as candidate targets for adjunctive antiresistance drug development. Keywords: Klebsiella pneumoniae, carbapenem resistance, whole genome sequencing, multi-omics, North West Nigeria.