ダプトマイシン
耐性をもたらす伝達性因子は知られていない。また他の抗生物質・抗菌薬に対する交差耐性はみられていない。
New derivatives of daptomycin (Figure 9) were originally generated by exchanging the third NRPS subunit (dptD) with the terminal subunits from the A54145 (Factor B1) or calcium-dependent antibiotic pathways to create molecules containing Trp13, Ile13, or Val13. dptD is responsible for incorporating the penultimate amino acid, 3-methyl-glutamic acid (3mGlu12), and the last amino acid, Kyn13, into the chain. This exchange was achieved without engineering the interpeptide docking sites. These whole-subunit exchanges have been coupled with the deletion of the Glu12-methyltransferase gene, with module exchanges at intradomain linker sites at Ala8 and Ser11, and with variations of natural fatty-acid side chains to generate over 70 novel lipopeptides in significant quantities; most of these resultant lipopeptides have potent antibacterial activities.
To synthesize the peptide portion of daptomycin, the mechanism of an NRPS is employed. The biosynthetic machinery of an NRPS system is composed of multimodular enzymatic assembly lines that contain one module for each amino acid monomer incorporated. Within each module are catalytic domains that carry out the elongation of the growing peptidyl chain. The growing peptide is covalently tethered to a thiolation domain; here it is termed the peptidyl carrier protein, as it carries the growing peptide from one catalytic domain to the next. Again, the apo-T domain must be primed to the holo-T domain by a PPTase, attaching a flexible phosphopantetheine arm to a conserved serine residue.