Efficient Synthesis of Clovibactin and Its Analogues: Promoting the Discovery of More Potent Antibiotics via Multiple Screenings

Increasingly, antimicrobial resistance has become a major concern for public health. The recently discovered cyclic depsipeptide, clovibactin, is a potential antibiotic candidate with potent activities against multidrug-resistant pathogens. It contains three d-amino acids, including a rare d-hydroxyasparagine residue. Herein, we present the efficient synthesis of the suitably protected d-hydroxyasparagine building block and the natural product clovibactin. Efforts have also been made by us to establish the structure–activity relationship (SAR) of clovibactin and to hunt for more active analogues. After three rounds of screening, the new compounds 30, 40, and 42 were found to exhibit higher antibacterial activity than clovibactin and were able to eradicate methicillin-resistant Staphylococcus aureus (MRSA). Their substantial efficacy was also demonstrated in a bactericidal activity assay, an in vitro time-killing assay, a hemolysis assay, and a potential resistance development evaluation. The improved antibacterial activity, low hematotoxicity, and resistance-resistant properties of analogues 30, 40, and 42 make them promising for further evaluation of drug-likeness and the development of next-generation antibiotics.