Strategies and tactics for the synthesis of lipid I and II and shortened analogues: functional building blocks of bacterial cell wall biosynthesis.

Covering: the literature up to 2022This study discusses various synthetic strategies for the synthesis of lipid II, the pivotal bacterial cell wall precursor. In detail, it examines different solution phase approaches, reviews various solid phase sequences, and evaluates enzymatic ventures. The underlying rationale, scope, limitations, and perspectives of these strategies are discussed. The focus is on the tactics and strategies towards the authentic peptidoglycan compound, as well as analogues thereof with shortened side chains, which are increasingly recognized as more beneficial surrogates with more favorable physicochemical properties.

Versatile synthesis of pathogen specific bacterial cell wall building blocks.

Full details on the design, strategies and tactics for development of a novel synthetic sequence to farnesyl lipid I and II analogs is reported. The modular route was based on a three coupling strategy involving an efficient solid phase synthesis of the elaborate peptide fragment, which proceeded with excellent yield and stereoselectivity and was efficiently applied for the convergent synthesis of 3-lipid I and II. Furthermore, the generality of this route was demonstrated by synthesis of 3-lipid I congeners that are characteristic for S. aureus and E. faecalis. All 3-lipid I and II building blocks were obtained in high purity revealing high spectroscopic resolution.

Synthesis of Tetramic Acid Fragments Derived from Vancoresmycin Showing Inhibitory Effects towards S. aureus.

An efficient route to various vancoresmycin-type tetramic acids has been developed. The modular route is based on an effective Fries-type rearrangement to introduce various appending acetyl residues. The minimum inhibitory concentration (MIC) values of the new tetramic acids against Staphylococcus aureus and Escherichia coli were determined, revealing that three of the new compounds exhibit antimicrobial activity against S. aureus. These bioactive compounds were structurally most closely related to the authentic vancoresmycin building block. Additionally, the compounds induced a lial-lux bioreporter, which responds to cell wall stress induced by antibiotics that interfere with the lipid II biosynthesis cycle. These data suggest the tetramic acid moiety to be a part of the vancoresmycin pharmacophore.