The cyclic lipopeptides comprise a number of clinically relevant classes of antibiotics that date back from the discovery of the polymyxins in 1947 to the recent introduction of the lipoglycopeptides. These natural products and natural product derivatives generally originate from soil-inhabiting producing organisms. They consist of peptide macrocycles that are modified with a lipid, and show great structural diversity owing to their non-standard biosynthetic pathways involving non-ribosomal synthesis and/or post-translational modifications.
In recent years the number of newly discovered classes of lipopeptide antibiotics with unique modes of action has declined and those that are found are generally not suitable for direct advancement to clinical development. Such natural products can however be used as starting point for chemical modifications to improve their drug-like properties. It is important that the antibiotic modes of action of these natural products are well understood.
Here, we describe the first synthesis and the working mechanism of the naturally occurring lipopeptide antibiotic laspartomycin C. We show that it inhibits the bacterial cell wall synthesis by binding a phospholipid precursor. In addition, we show the molecular details of that binder interaction through a crystal structure. There are currently no clinically used antibiotics that operate via this mode of action.
In addition, we provide a detailed mechanistic study of a nisin lipopeptide, a chemical derivative of the potent natural product antibiotic nisin. The nisin lipopeptide maintains the antibiotic properties of nisin, but has superior drug-like properties. Like nisin, the nisin lipopeptide targets lipid II, often described as the bacterial “Achilles Heel” to induce detrimental defects in the bacterial membrane.