SadA gene copy number variation and subtype-associated sulfonamide transformation in Paenarthrobacter sp. R1: insights from multi-omics and molecular dynamics.

Abstract

Microbial degradation is crucial for eliminating sulfonamide antibiotics (SAs) from environments, yet the contributions of gene copy number and subtype diversity to SA transformation remain unclear. Here, we characterize Paenarthrobacter strain R1, a hyper-degrader exhibiting rapid, broad-spectrum SA biotransformation. Genomic analysis revealed an expanded sadA repertoire comprising six copies (one Type I and five Type II), suggesting a potential gene dosage effect on SA degradation. Transcriptomic analysis revealed preferential induction of Type II-associated sad genes during sulfamethoxazole transformation, with little or no induction of Type I-associated genes. Heterologous co-expression assays revealed distinct subtype-associated transformation profiles. The Type II strain rapidly transformed sulfamethoxazole and sulfadiazine, whereas the Type III strain, carrying a variant from another SA-degrading Paenarthrobacter strain, achieved more extensive sulfamethazine transformation. In contrast, the Type I strain showed no significant SA transformation under the tested conditions. Molecular dynamics simulations and free-energy calculations suggested that differences in SA transformation may be associated with the precise spatial alignment of substrates relative to the FMN cofactor, rather than merely overall predicted binding affinity. Type II and Type III variants exhibited distinct residue-interaction networks involving polar anchoring and hydrophobic confinement that may favor catalytically relevant substrate geometries for specific SAs. Conversely, Type I exhibited greater conformational fluctuations, potentially affecting productive substrate positioning. This study integrates multi-omics and structural dynamics to propose a biotransformation model highlighting the potential contributions of sadA copy number, subtype diversity, and structural determinants to substrate-dependent SA degradation.

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