Daptomycin and Related Lipopeptides Produced by Fermentation, Chemical Modification, and Combinatorial Biosynthesis

Genome mining for drug discovery: cyclic lipopeptides related to daptomycin

“…Laspartomycin has C15:Δ2; friulimicin C13–15:Δcis3; taromycin C8:Δ2,4; and malacidin C10–11:Δ2,4. The fatty acid chain length and degree of unsaturation can influence the biological activities of cyclic lipopeptide antibiotics, and are thus important targets for combinatorial biosynthesis as well as chemical semi-synthesis (Baltz et al., 2005 ; Baltz, 2014 b, 2014d ). FAAL and ACP genes are contiguous and just upstream of the first NRPS genes in the daptomycin, A54145, telomycin BGCs (Fig.…”

“…Incremental resistance to daptomycin in low G + C pathogenic Gram + bacteria is mediated by mutations in a number of genes that result in alterations in cell membrane charge or cell wall thickness (Baltz, 2009 , 2014d ). None of the genes involved in these mechanisms are observed in lipopeptide BGCs.…”

“…None of the genes involved in these mechanisms are observed in lipopeptide BGCs. The high G + C Gram + actinomycetes tend to be intrinsically resistant to daptomycin by expressing hydrolases that cleave the fatty acid tail, or the depsipeptide bond, and many show secondary peptide bond cleavages (D'Costa et al., 2006 , 2012 ; Baltz, 2014d ). These mechanisms often result in MICs > 256 μg/ml.…”

“…This aspect of lipopeptide BGCs should facilitate successful combinatorial biosynthesis of compounds with improved antibacterial properties and toxicity profiles, and possible beneficial changes in MOA, without jeopardizing the viability of the recombinants producing the new molecules. This may help explain the high success rates of producing novel lipopeptides by combinatorial biosynthesis at Cubist Pharmaceuticals (Baltz, 2014 b, 2014 c, 2014d ). So far, little is known about the substrate specificities and possible cross-resistance patterns expressed by lipopeptide ABC transporters.…”

“…Both de novo discovery and combinatorial biosynthesis can be coupled with medicinal chemistry to further explore structure–activity relationships (SAR) for drug discovery and development. An example of an NRPS-derived commercial product that has been developed, and further modified by these approaches is the cyclic lipopeptide antibiotic daptomycin (Debono et al., 1988 ; Baltz, 2014 b, 2014 c, 2014 d; Knight-Connoni et al., 2016 ).…”