Mycoplasma pneumoniae is a significant pathogen responsible for community-acquired respiratory infections in children and adolescents, with the rising prevalence of macrolide-resistant M. pneumoniae (MRMP), particularly in Asia, presenting critical treatment challenges. Our previous study inferred that a macrolide efflux pump may contribute to macrolide resistance in M. pneumoniae in addition to the common point mutations in 23S rRNA gene. This study aimed to define the specific pump and confirm its role. Through comparative genomic analysis, we identified a candidate gene, MPN₀80, encoding an ABC transporter permease, which was further characterized using phylogenetic analysis, AlphaFold-based structural modeling, and biochemical assays. Overexpression of MPN₀80 from an erythromycin-resistant isolate in the erythromycin-sensitive M129 resulted in a significant increase in minimum inhibitory concentrations (MICs) from <0. 125 µg/mL to 1 µg/mL, while similar overexpression of MPN₀80 derived from M129 did not affect MICs. Notably, this resistance mechanism operates independently of M. pneumoniae virulence factors, as evidenced by unaltered colonization capacity in NCI-H292 cells and consistent immune response patterns across both strains. Our findings establish MPN₀80 as a novel determinant of macrolide resistance functioning associated with enhanced ATPase activity. These insights into non-classical resistance mechanisms may guide future diagnostic and therapeutic strategies against MRMP.
Li et al. (Sun,) studied this question.
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