Chemoenzymatic Modification of Daptomycin: Aromatic Group Installation on Trp1

Area of Science:

• Medicinal Chemistry
• Microbiology
• Enzymatic Synthesis

Background:

• Daptomycin is a crucial antibiotic for Gram-positive infections, including resistant strains like MRSA and VRE.
• The rise of daptomycin resistance necessitates the development of novel analogs.
• Previous work indicated aromatic substitutions on daptomycin's tryptophan enhance potency.

Purpose of the Study:

• To generate novel daptomycin analogs with potentially improved antibacterial activity.
• To explore the enzymatic derivatization of daptomycin using prenyltransferase CdpNPT.
• To assess the antibacterial efficacy of these new analogs against resistant pathogens.

Main Methods:

• Utilized the prenyltransferase CdpNPT to attach various aromatic groups to daptomycin's tryptophan residue.
• Employed analytical and scaled-up reactions for compound synthesis and purification.
• Conducted in vitro antibacterial assays to evaluate the potency of purified analogs.

Main Results:

• CdpNPT successfully transferred diverse aromatic groups onto daptomycin.
• Aromatic substitutions were achieved at multiple positions (N1, C2, C5, C6) of the Trp1 residue.
• Six purified analogs demonstrated significant potency against both daptomycin-susceptible and resistant Gram-positive bacteria.

Conclusions:

• Enzymatic installation of aromatic groups onto daptomycin's Trp1 residue is feasible.
• Aromatic substitution represents a viable strategy for generating potent daptomycin analogs.
• These findings offer a promising avenue for combating challenging Gram-positive bacterial infections.