Daptomycin: putative new mechanisms of action and resistance evolved from transcriptome data mining

Daptomycin (Cubicin) is a newly approved effective antibiotic for treatment of the complex skin infections and structure skin infections caused by Gram-positive bacteria, heart infections and bacteremia caused by Staphylococcus aureus which are major scourge of nosocomial-infection and community-infection. However, treatment failures due to lowering of the drug sensitivity are invariantly reported. But the mechanism of action and the contribution factors of decreased sensitivity to daptomycin remain elusive and contentious. In-depth analysis of genome-wide microarray based transcriptome data may facilitate pinpointing the daptomycin targets and regulatory networks pivotal to its efficacy. In this paper, we summarized the structure, mechanism of action of daptomycin and focused on the specific changes in transcriptome of Staphylococcus aureus response to daptomycin to mine potential targets and mechanism of daptomycin resistance. We propose a working model of daptomycin action sharply contrasting with the prevalent notion, that daptomycin exerts its activity by inducing autolysis of Staphylococcus aureus. The detailed genes and related pathways are enumerated. This merits further experiment validation and might benefit future rational use of daptomycin and the development of next generation of lipopeptide antibiotics. (C) 2009 Wolters Kluwer Health | Lippincott Williams & Wilkins