Recently mutations in the phospholipid biosynthesis genes cardiolipin synthase (cls2) and CDP-diacylglycerol-glycerol-3-phosphate 3 phosphatidyltransferase (pgsA) have been found in clinical DNS strains . Another altered
protein sometimes found in DNS strains is YycG, which is one of two components of a response regulator system involved in the metabolism of the cytoplasmic membrane and cell wall . The proteins RpoB and RpoC, which comprise the β and β′ subunit of RNA polymerase, have also been found with amino acid substitutions in DNS S. aureus strains Cytoskeletal Signaling inhibitor . Recently, a single nucleotide polymorphism in rpoB from a laboratory derived DNS S. aureus was associated with decreased negative surface charge, increased cell wall Bcr-Abl inhibitor thickness, and both vancomycin and daptomycin heteroresistance . Additionally, increased expression of the dltABCD operon increases d-alanylation of cell wall teichoic acids contributing to an increase in positive surface charge . CH5183284 clinical trial Recent work has also suggested membrane proteins may augment the bactericidal effects of daptomycin, and alteration or loss of these proteins may contribute to DNS . It has also been proposed that changes in carotenoid biosynthesis in S. aureus can increase membrane rigidity and
contribute to increases in daptomycin MIC values . Overall, DNS S. aureus strains show altered membrane potential, changes in membrane fluidity, increased positive membrane surface charge, and decreased membrane depolarization [10–15]. It is hypothesized that the increase Morin Hydrate in cytoplasmic membrane surface charge repels the active daptomycin-Ca2+ complex and therefore impedes interaction of daptomycin with the membrane [10, 20]. There are likely other genetic changes that contribute to DNS in S. aureus as strains exhibiting elevated MICs often have only some of the changes mentioned above [21–24].
There is still much room for discovery of novel cell membrane and genetic changes in DNS strains of S. aureus. We have observed that some of the S. aureus strains identified as DNS by the clinical microbiology laboratory at our institution using Microscan® (Dade Behring, Deerfield, IL, USA) were actually susceptible via broth microdilution following passage on antibiotic free agar or time being stored at −80 °C. This observation led us to question the stability of these isolates. Additionally, previous in vitro work we have done with DNS strains has demonstrated variable activity of daptomycin [25, 26]. In some cases, daptomycin regimens of 10 mg/kg per day maintain antibacterial activity and led us to hypothesize that some S.