Description:
<jats:title>Abstract</jats:title><jats:p><jats:bold>Resisting resistance</jats:bold>: Acidic lipopeptide antibiotics are very effective in fighting multidrug‐resistant Gram‐positive bacteria, including methicillin‐resistant <jats:italic>Staphylococcus aureus</jats:italic> and vancomycin‐resistant <jats:italic>enterococci.</jats:italic> The structural diversity of these lipopeptides, including daptomycin, which is already in clinical use, is depicted in this review. Engineering approaches to yield novel lipopeptides and tailoring events facilitating structural variety are presented.<jats:boxed-text content-type="graphic" position="anchor"><jats:graphic xmlns:xlink="http://www.w3.org/1999/xlink" mimetype="image/gif" position="anchor" specific-use="enlarged-web-image" xlink:href="graphic/mcontent.gif"><jats:alt-text>magnified image</jats:alt-text></jats:graphic></jats:boxed-text></jats:p><jats:p>Acidic lipopeptide antibiotics are a new class of potent antibiotics, which includes daptomycin, A54145, calcium‐dependent antibiotics (CDAs), friulimicins/amphomycins, laspartomycin/glycinocins and others. The importance of this novel class is exemplified by the success story of the clinically approved daptomycin, which is used for the treatment of skin infections and bacteremia caused by multidrug‐resistant bacteria, including methicillin‐resistant <jats:italic>Staphylococcus aureus</jats:italic> and vancomycin‐resistant <jats:italic>enterococci</jats:italic>. The potency of acidic lipopeptides is inherent in their chemical structure. The nonribosomally synthesized peptide cores consist of eleven to 13 amino acids, which are rigidified by the formation of a ten‐membered ring. An N‐terminal fatty acid, which facilitates insertion into the lipid bilayer of bacterial membranes, completes the structure. All these antibiotics contain multiple nonproteinogenic amino acids as well as different lipid tails; this yields remarkable structural diversity. This review summarizes the observed structural variety through a detailed description of the composition of the acidic lipopeptides. Furthermore, engineering approaches towards novel lipopeptides are presented. Recent discoveries in the field of tailoring enzymes, which enable structural plurality mainly by amino and fatty acid precursor biosynthesis, are highlighted.</jats:p>