Abstract

Gram negative bacteria contain one more outer membrane as an extra layer of protection compared with Gram positive bacteria, which posts more challenge to the treatment. Four of Gram-negative bacteria are on the list of most urgent threats highlighted by Infectious Disease Society of America1. The last-resort treatment for multidrug-resistant Gram-negative infections, colostin, also started to fail in the treatment of resistant strains2. 

The development of new antibiotics against Gram negative pathogens is urgently desired. With the new methodologies such as genome mining, high-throughput screening, there are some promising candidates developed and klebsazolicin is one of them3-4. However, there are still some drawbacks of klebsazolicin such as narrow spectrum and uptaking limitation needed to overcome5-6. As an optional method to solve these problems, biosynthesis achieved a great success in synthesizing klebsazolicin, but it showed inadequacy in post-translational modification, which limits development of mutated klebsazolicin. However, another optional method, chemical synthesis, has fewer limitations in modification and has achieved lots of success in synthesizing and modifying polypeptide and protein especially with the development of solid phase peptide synthesis (SPPS) and chemical ligation, which is another option for the synthesis and modification of klebsazolicin. 

Accordingly, we designed a chemical strategy to synthesize and modify klebsazolicin based on its antibacterial mechanism. Klebsazolicin is made up of normal amino acids, one amidine, three thiazoles and one oxazole, we split it to five kinds of building blocks. After SPPS and chemical reaction on resin, klebsazolicin will be synthesized. Optimization of antibacterial spectrum and uptaking ability of klebsazolcin can be achieved by introduction of conformation constrain and tunning of π-π stacking interaction based on antibacterial mechanism of klebsazolicin.

Reference:

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