Antimicrobial resistance (AMR) is one of the major challenges humans are facing this century. Understanding the mechanisms behind the rise of AMR is therefore crucial to tackle this global threat. Transition metals are essential for all life forms, while their presence also represents an environmental factor linked to the development of resistance and tolerance in environmental bacteria. A deeper understanding of how transition metals affect bacterial physiology and drug susceptibility will be beneficial for our knowledge in AMR and the discovery of potential therapeutic targets. During my PhD, I investigated the impact of copper, cobalt and nickel on the physiology and drug susceptibility of Mycobacterium abscessus (Mabs), a fast-growing non-tuberculous mycobacterium that is well known for its extreme level of AMR. The effects of transition metals on bacterial growth and intracellular metallomic homeostasis were first studied, and I found that transition metal treatment could alter the minimum inhibitory concentration (MIC) of Mabs to different antibiotics and their killing kinetics. A multi-omics strategy was then designed combining RNA sequencing, bioenergetics, targeted and untargeted metabolomics with liquid chromatography-mass spectrometry (LC-MS) and phenotypic assays to further investigate the mechanisms behind the effects of transition metals. I found that Mabs was able to reprogramme its central carbon metabolism and upregulate the glyoxylate shunt as a strategy to counteract the impact of Co and Ni influx, and induction of WhiB7 in response to metal stresses could be the key response that led to higher AMR levels. Meanwhile, Co and Ni treatment enhanced the uptake of clarithromycin into bacterial cells and caused a reduced MIC for this antibiotic. This thesis provides new insights into the tolerance mechanisms of Mabs and highlight the important roles of the glyoxylate shunt and the WhiB7 regulatory system in Mabs tolerance to transition metals and its AMR.