A facile and selective derivatization approach on kynurenine-NH2 in daptomycin, leading to the discovery of hexakynomycin to combat multidrug-resistant Gram-positive pathogens especially daptomycin-resistant bacteria.

Wide-spread use of daptomycin unavoidably resulted in the emergence of daptomycin-resistant pathogens. In the hunt for more active daptomycin derivatives through medicinal chemistry studies, we established a concise semisynthetic approach to modify the L-Kyn13 on daptomycin specifically and effectively. Here, 19 novel derivatives with certain diversity were designed and synthesized to perform a comprehensive SAR study on this underestimated position. The optimal compound, termed "hexakynomycin", as the new generation of daptomycin-based antibiotic candidate exhibited 4->125-fold higher activity against methicillin-susceptible S. aureus (MSSA), methicillin-resistant S. aureus (MRSA), vancomycin-intermediate resistant S. aureus (VISA), and vancomycin-resistant Enterococci (VRE), including daptomycin-resistant strains, compared with that of daptomycin. Greater membrane binding capacity rendered hexakynomycin better activity and special antibiotic property. Hexakynomycin also demonstrated a better pharmacokinetic profile, good safety features and good pharmacodynamics properties. This work provided an effective modification strategy aiming at daptomycin which provided significant insights and showed great promise for the next generation of daptomycin derivatives.