The development of variation-based rifampicin resistance in Staphylococcus aureus deciphered through genomic and transcriptomic study.

Rifampicin (RIF) resistance imposes a challenge on the antimicrobial treatment of pathogen infections. Figuring out the development mechanism of RIF resistance is critical to improving antimicrobial therapy strategy in clinics and biological treatment strategy of RIF polluted sewage in environmental engineering. The RIF resistance development of Staphylococcus aureus (S. aureus) with exposure to RIF at sub-inhibitory concentrations was comprehensively investigated via genomic and transcriptomic approaches in this study. RIF minimal inhibitory concentration (MIC) for S. aureus rapidly increased from 0.032 to 256 mg/L. Membrane permeability decrease, biofilm formation enhancement, and ROS production increase associated with RIF resistance were observed in RIF-induced strains. Through comparative genomic analysis, mutations in rpoB and rpoC were considered to be associated with RIF resistance in S. aureus mutants. Pan-genome-wide single-nucleotide variant analysis indicated that mutations at rpoB-1412, rpoB-1451, and rpoB-1457 were prevalent in 13849 public genomes of S. aureus, while mutations at rpoB-2256, and rpoC-3092 were first discovered in this study. The panorama of adaptative alteration of cellular physiological processes was observed via transcriptomic analysis. The oxidation pressure responses, metabolism, transporters, virulence factors, and multiple steps of DNA and RNA machinery were found to be perturbed by RIF in S. aureus.