Daptomycin: new insights into an antibiotic of last resort

In addition to disrupting the localization of enzymes involved in cell wall biosynthesis, daptomycin also inhibits expression of the alternative Pbp2a, which is required for peptidoglycan biosynthesis by MRSA strains in the presence of β-lactam antibiotics(5). Enhanced approaches to daptomycin therapy are needed because, although the antibiotic is safe, therapeutic success rates vary with 24% of endocarditis cases and 30% of osteomyelitis cases failing to respond to the antibiotic(7). [...]efforts to improve efficacy are required and have included the supplementation of daptomycin with a β-lactam to benefit from the see-saw effect(2). In Streptococcus mitis, the DNS phenotype is associated with a dramatic loss of membrane PG and cardiolipin, which are replaced by phosphatidic acid, and results in significantly increased membrane fluidity(13). [...]it remains unclear whether the DNS phenotype is conferred by charge repulsion, membrane fluidity or a combination of both and the degree to which the genetic background of isolates influences these mechanisms. Analysis of DNS Staphylococcus aureus by Gaupp and colleagues found decreased activity of the tricarboxylic acid (TCA) cycle but increased production of pyrimidines and purines, and elevated synthesis of precursors involved in peptidoglycan and teichoic acid biosynthesis(14).