Daptomycin: Mechanism of action, mechanisms of resistance, synthesis and structure-activity relationships

Daptomycin is a cyclic lipodepsipeptide antibiotic that is a mainstay for the treatment of serious infections caused by Gram-positive bacteria, including methicillin-resistant Streptococcus aureus and vancomycin resistant enterococci. It is one of the so-called last-resort antibiotics that are used to tackle life-threatening infections that do not respond to first-line treatments. However, resistance to daptomycin is eroding its clinical efficacy motivating the design and/or discovery of analogues that overcome resistance. The strategy of antibiotic analogue synthesis has been used to overcome bacterial resistance to many classes of antibiotics such as the β-lactams. Pursuing this strategy with daptomycin requires a detailed understanding of daptomycin's action mechanism and synthesis. Here, we discuss the action mechanism of daptomycin in a holistic manner and expand this discussion to rationalize conferred modes of resistance. Synthetic efforts, both chemical and biological, are discussed in detail and the structure-activity relationship emanating from these works is distilled into a usable model that can guide the design of new daptomycin analogues.