Down-regulation of the two-component system and cell-wall biosynthesis-related genes was associated with the reversion to daptomycin susceptibility in daptomycin non-susceptible methicillin-resistant Staphylococcus aureus

• Published in: European journal of clinical microbiology & infectious diseases 2017-10, Vol.36 (10), p.1839-1845
• Main Authors: Iwata, Y., Satou, K., Tsuzuku, H., Furuichi, K., Senda, Y., Sakai-Takemori, Y., Wada, T., Fujita, S., Miyake, T., Yasuda, H., Sakai, N., Kitajima, S., Toyama, T., Shinozaki, Y., Sagara, A., Miyagawa, T., Hara, A., Shimizu, M., Kamikawa, Y., Kaneko, S.
• Format: Article
• Language: English
• Subjects: Aged; Anti-Bacterial Agents - pharmacology; Biomedical and Life Sciences; Biomedicine; Biosynthesis; Cell surface; Cell Wall - metabolism; Cell walls; Daptomycin; Daptomycin - pharmacology; DNA Mutational Analysis; Drug resistance; Female; Gene expression; Gene Expression Profiling; Gene Expression Regulation, Bacterial; Genes; Genomes; Genotype; Gram-positive bacteria; Humans; Internal Medicine; Medical Microbiology; Methicillin; Methicillin-Resistant Staphylococcus aureus - drug effects; Methicillin-Resistant Staphylococcus aureus - genetics; Methicillin-Resistant Staphylococcus aureus - isolation & purification; Missense mutation; Mutation; Mutation, Missense; Original Article; Phenotype; Reversion; Staphylococcus aureus; Staphylococcus infections; Surface charge; Transcription
• ISSN: 0934-9723; 1435-4373
• DOI: 10.1007/s10096-017-2999-3

Daptomycin (DAP) is widely used in the treatment of methicillin-resistant Staphylococcus aureus (MRSA) infection. The emergence of DAP non-susceptible MRSA strains during therapy is a major concern in clinical settings. Recent studies revealed that MRSA spontaneously reverts to a subsequent methicillin-susceptible S. aureus (MSSA) strain. However, it is not clear whether DAP non-susceptible MRSA has the ability to revert to a susceptible strain. We obtained an MRSA strain pair, DAP non-susceptible strain and subsequent DAP susceptible strain, from a patient. To understand the underlying mechanism by which DAP non-susceptible MRSA reverts to a susceptible strain, we performed genetic and phenotypic analysis in the strain pair. Although whole-genome analysis revealed four missense mutations, including L826F in mprF , in both strains, the net cell-surface charge was similar between the DAP non-susceptible and susceptible strains. However, the thickness of the cell wall was higher in the DAP non-susceptible strain, which was decreased to the same level as the control after reversion to the DAP susceptible strain. Moreover, the non-susceptible strain showed higher mRNA expression of the two-component system (TCS), such as VraSR , yycG and GraS , with the up-regulated transcription levels of cell-wall biosynthesis-related genes. The expression levels of those genes were decreased after reversion to the susceptible strain. These results indicated that DAP non-susceptibility due to up-regulation of the TCS and cell-wall biosynthesis-related genes may be reversible by the discontinuation of DAP, leading to reversion to the DAP susceptible phenotype.