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

ABSTRACT: Daptomycin is an extensively used anti-staphylococcal agent due to the rise in methicillin-resistant Staphylococcus aureus. However, both laboratory-derived and clinical decreased susceptibility isolates have been described, but the mechanism(s) of resistance is poorly understood. To further understand daptomycin resistance, comparative genome sequencing, transcriptomics, ultrastructure ,and cell envelope studies were carried out on two relatively higher level (4 and 8 ug/ml-1) laboratory-derived daptomycin-resistant strains (strains CB1541 and CB1540 respectively) compared to their methicillin-resistant parent strain (CB1118;MW2). Genes altered in their expression common to both transcriptomes included some involved in glycine betaine accumulation, mscL, ure genes, femH, spa and smpB. However, the CB1541 transcriptome was further characterized by upregulation of various heat shock chaperone and protease genes, consistent with a mutation in clpP, and lytM and sceD. Both strains showed slow growth, and strongly decreased autolytic activity that appeared to be mainly due to decreased autolysin production. In contrast to previous common findings, we did not find any mutations in phospholipid biosynthesis genes, and it appears there are multiple pathways to and factors in daptomycin resistance.

ORGANISM(S): Staphylococcus aureus

PROVIDER: GSE40753 | GEO | 2012/10/01

SECONDARY ACCESSION(S): PRJNA174813

REPOSITORIES: GEO

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Project description:Objectives: Development of daptomycin resistance (DAPR) in Staphylococcus aureus is associated with clinical treatment failures. Mechanism(s) of such resistance has not been clearly defined. Methods: We studied an isogenic daptomycin-susceptible (DAPS) and daptomycin-resistant (DAPR) S. aureus strain pair (616; 701) from a patient with relapsing endocarditis during daptomycin treatment, using comparative transcriptomic and proteomic techniques. Results. Minor differences in genome content were found between strains by DNA hybridization. Transcriptomic analyses identified a number of genes differentially expressed in important functional categories: cell division, metabolism of bacterial envelopes and global regulation. Of note, the DAPR isolate exhibited reduced expression of the major cell wall autolysis gene coincident with upregulation of genes involved in wall teichoic acid production. Using quantitative (q)RT-PCR on gene cadre putatively involved in cationic peptide resistance, we formulated a putative regulatory network compatible with microarray data-sets, mainly implicating bacterial envelopes. Of interest, qRT-PCR of this same gene cadre from two distinct isogenic DAPS/DAPR clinical strain pairs revealed evidence of other strain dependent networks operative in the DAPR phenotype. Comparative proteomics of 616 vs 701 revealed differential abundance of proteins in various functional categories including: cell-wall associated targets and biofilm-formation proteins. Phenotypically, strains 616 and 701 showed major differences in ability to develop bacterial biofilms in presence of the antibacterial lipid, oleic acid. Conclusions: Compatible with previous in vitro observations, in vivo acquired DAPR in S. aureus is a complex, multistep phenomenon allowing for: i) strain dependent phenotypes; ii) transcriptome adaptation; and iii) modification of lipid and protein content of cellular envelopes. Daptomycin suceptible strain vs daptomycin non suceptible strain after daptomycin treatment

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

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