Additional Routes to Staphylococcus aureus Daptomycin Resistance as Revealed by Comparative Genome Sequencing, Transcriptional Profiling, and Phenotypic Studies

摘要: Daptomycin is an extensively used anti-staphylococcal agent due to the rise in methicillin-resistant Staphylococcus aureus, but mechanism(s) of resistance poorly understood. Comparative genome sequencing, transcriptomics, ultrastructure, and cell envelope studies were carried out on two relatively higher level (4 8 µg/ml−1) laboratory-derived daptomycin-resistant strains (strains CB1541 CB1540 respectively) compared their parent strain (CB1118; MW2). Several mutations found strains. Both had same two-component system genes walK agrA. In also detected ribose phosphate pyrophosphokinase (prs) polyribonucleotide nucleotidyltransferase (pnpA), a hypothetical protein gene, intergenic region. there clpP, ATP-dependent protease, different genes. The transcriptome was characterized by upregulation cap (capsule) operon genes, involved accumulation compatible solute glycine betaine, ure urease operon, mscL encoding mechanosensitive chanel. Downregulated included smpB, femAB femH formation pentaglycine interpeptide bridge, synthesis fermentation, spa A. Genes altered expression common both transcriptomes some betaine accumulation, mscL, femH, smpB. However, further various heat shock chaperone protease consistent with mutation lytM sceD. showed slow growth, strongly decreased autolytic activity that appeared be mainly autolysin production. contrast previous findings, we did not find any phospholipid biosynthesis it appears are multiple pathways factors daptomycin resistance.