Macrolide resistance in Mycobacterium abscessus: current insights and future perspectives

Abstract

Mycobacterium abscessus (MAB) is a rapidly growing, non-tuberculous mycobacterium that has emerged as a significant pathogen in both pulmonary and extrapulmonary infections. It is rising in prevalence, especially among individuals with underlying lung conditions such as cystic fibrosis and chronic obstructive pulmonary disease, highlighting its growing clinical importance. The treatment of MAB infections is notoriously challenging due to intrinsic resistance to many antibiotics and low cure rates, typically <50%. Macrolides are a cornerstone in the treatment of MAB infections because regimens that include effective macrolide therapy are associated with higher cure rates. However, MAB possesses intrinsic and acquired drug resistance mechanisms against macrolides, complicating drug susceptibility testing and selection of highly effective treatment regimens. This review aims to provide a summary of the current understanding of macrolide resistance mechanisms in MAB. We explored the epidemiology of resistance in different countries and the molecular mechanisms involved. We have highlighted the variability in sensitivity of existing markers to predict phenotypic macrolide drug resistance across different countries, suggesting the involvement of unknown resistance mechanisms. By synthesizing current knowledge and identifying gaps in the literature, this review seeks to inform clinical practice and guide future research efforts in the fight against MAB drug resistance.

Figure 1.

Mechanisms of macrolide resistance in M. abscessus and evolutionary changes in erm(41). (a) Two primary mechanisms of macrolide resistance in MAB. Inducible resistance is mediated by erm(41) with a 28T allele, which is up-regulated in response to macrolides via whiB7, leading to ribosomal methylation and reduced drug binding. MAB remain susceptible at early time points (Day 3) but develop resistance later, typically measured by Day 14. Acquired resistance occurs through mutations in rrl, leading to macrolide resistance detected as early as Day 3. (b) Schematic representation of macrolide resistance mechanisms. Macrolides inhibit MAB growth by binding to the 50S ribosomal subunit. In erm(41)-mediated resistance, whiB7 senses macrolides and activates erm(41) expression, leading to ribosomal methylation and reduced macrolide binding. In acquired resistance, rrl mutations disrupt macrolide binding to the ribosome, conferring resistance. (c) Phylogenetic reconstruction of macrolide resistance evolution in the MAB complex. The ancestral erm(41) 28 T allele, associated with inducible macrolide resistance (black), was retained in MAB subsp. abscessus and subsp. bolletii. A lineage-specific mutation (28T→28C) led to macrolide susceptibility. In MAB subsp. massiliense, erm(41) was truncated, resulting in loss of inducible resistance.

Figure 2.

The relative proportions of the three M. abscessus subspecies across different geographic regions. (a) Pie charts illustrating the composition of subsp. abscessus, subsp. massiliense and subsp. bolletii in various countries/regions. (b) Bar plots displaying the relative proportions, highlighting the increased prevalence of subsp. massiliense in Asia and subsp. bolletii in Europe.

Figure 3.

Sensitivity of rrl mutations in predicting macrolide resistance on Day 3 across different studies and geographic regions. A stacked bar chart showing the proportion of macrolide-resistant isolates on Day 3 that harbor rrl mutations versus those without rrl mutations. Each bar represents a study or dataset, with the total number of resistant isolates on Day 3 indicated on the right. The proportion of rrl mutants varies across studies, with some datasets (e.g. Thailand 2023 and China 2022) showing complete correlation between rrl mutations and resistance, while others (e.g. China 2021 and Brazil 2018) exhibit a lower association. These findings highlight variability in the predictive value of rrl mutations for early macrolide resistance.