Mycobacterium abscessus is a nontuberculous mycobacterium recognized as an emerging opportunistic pathogen that poses a growing clinical challenge worldwide. It causes recalcitrant pulmonary and extrapulmonary infections and is characterized by morphotype switching and biofilm-forming capacity. These phenotypic features are considered important virulence determinants; however, the genetic factors underlying phenotypic variability remain poorly understood. The biofilm-forming capacity, mutations associated with morphotype variation, and genetic determinants linked to deficient biofilm formation were investigated in 58 clinical Mycobacterium abscessus isolates recovered from non-cystic fibrosis patients. For biofilm-forming capability, 41.4% (n = 24) of isolates were categorized as strong producers, 51.7% (n = 30) as moderate producers, and 6.9% (n = 4) as weak producers. Smooth morphotype isolates produced significantly greater biofilm biomass than rough isolates (p = 0.006). Genomic analysis demonstrated that the rough morphotype was significantly associated with genetic alterations, including point mutations, insertions/deletions (indels), and large genomic deletions disrupting genes involved in glycopeptidolipid (GPL) biosynthesis, particularly mps1 and mps2. Longitudinal analysis of serial isolates obtained from a single patient revealed a massive 37.6-kb deletion and loss-of-function mutations in genes associated with stress response (lat), metabolism (atsA), and membrane transport (mspA) among weak biofilm-forming isolates. Notably, the mutations potentially contributing to morphotype switching and altered biofilm-forming capacity occur spontaneously across these clinical isolates. Collectively, these findings identify genomic determinants associated with morphotype transition and biofilm attenuation in M. abscessus, highlighting potential targets for strategies aimed at disrupting biofilm formation and improving the management of M. abscessus infections.
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