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

Abstract

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.

Gut microbiota–derived D-serine protects against acute kidney injury

“…The following primers were used: Ccl2, 5′-CTTCCTCCACCACCATGCA-3′ and 5′-CCAGCCGGCAACTGTGA-3′; Havcr1, 5′-AGGAAGACCCACGGCTATTT-3′ and 5′-TGTCACAGTGCCATTCCAGT-3′ (catalog Mm00506686; Applied Biosystems TaqMan Gene Expression Assays). Data were analyzed using the ΔΔCt method (32).…”

Involvement of p38MAPK in Impaired Neutrophil Bactericidal Activity of Hemodialysis Patients

“…HD patients with S. aureus bacteremia are known to be at notable risk for endocarditis, which is a life‐threating infectious disease . Other potential risk factors for infection include high burden of coexisting illnesses, hypoalbuminemia, immunosuppressive therapy, nephrotic syndrome, uremia, anemia, malnutrition and change of susceptibility of bacteria to antibiotics . However, the precise reasons why HD patients are susceptible to bacteremia remain to be clarified.…”

Daptomycin Resistance in Clinical MRSA Strains Is Associated with a High Biological Fitness Cost

“…In fact, a similar clinical case has been then reported in where a heterogeneous MRSA DAP resistance isolate was selected under DAP treatment followed by a susceptible DAP phenotype strain when the antibiotic treatment was changed, however, the mechanistic bases of this phenotypic conversion were not further explored ( Capone et al, 2016 ). Moreover, in a recent clinical MRSA strain pair obtained from a patient, it was demonstrated that DAP resistance reversion to a susceptible phenotype was obtained after DAP discontinuation, mechanistically associated with downregulation of cell wall associated genes ( Iwata et al, 2017 ). These observations including ours, support the common notion that DAP resistant strains have the ability to revert to susceptible once DAP treatment is discontinued and switched to an alternative antimicrobial therapy.…”