The rapid expansion of antimicrobial resistance (AMR) among Gram-negative pathogens presents a major clinical challenge, particularly in vulnerable populations such as infants. The dissemination of resistance is often mediated by mobile genetic elements (MGEs) that can mobilise antimicrobial resistance genes (ARGs) both within and between genomes. The insertion sequence (IS) IS 26 , is a MGE with the ability to replicate itself and associated ARGs, create translocatable units (TU), and produce tandem arrays of ARGs. Here we present the 18-week in vivo evolution of a community-acquired multi-drug resistant (MDR) Escherichia coli colonising an infant gut, characterised by a de-amplification of an IS 26 -mediated tandem array of ARGs. The hybrid-assembled ancestral and descendant strain genomes show an evolutionary rate of 10.22 SNPs per genome per year. Independent analysis of the hybrid genome assembly, and of Oxford Nanopore Technologies (ONT) and Illumina read-mapping support the existence of at least five copies of a TU (Tn 3 -like( tnpA )- tetR-tetA-yedA- ΔTn 1721 ( tnpA ) - IS 26 - aac(6’)-Ib-cr-bla _OXA-1 - Δ catB3 -IS 26 ) in the ancestor and only one in the descendant. Despite de-amplification, no change in fitness (p = 0.275) and piperacillin-tazobactam susceptibility (TZP) was observed. In contrast, gentamicin susceptibility increased, in the absence of known associated mutations. This study provides insight into IS 26 -mobility dynamics in vivo and their implications for AMR, within the rapidly changing environment of the neonatal gut.

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