Synthesis and Preliminary Biological Characterization of New Semisynthetic Derivatives of Ramoplanin

Abstract

Ramoplanin is a glycolipodepsipeptide antibiotic active against Gram-positive bacteria including vancomycin-resistant enterococci. Ramoplanin inhibits bacterial cell wall biosynthesis by a mechanism different from that of glycopeptides and hence does not show cross-resistance with these antibiotics. The systemic use of ramoplanin has been so far prevented because of its low local tolerability when injected intravenously. To overcome this problem, the fatty acid side chain of ramoplanin was selectively removed and replaced with a variety of different carboxylic acids. Many of the new ramoplanin derivatives showed antimicrobial activity similar to that of the natural precursor coupled with a significantly improved local tolerability. Among them the derivative in which the 2-methylphenylacetic acid has replaced the di-unsaturated fatty acid side chain (48) was selected as the most interesting compound and submitted to further in vitro and in vivo characterization studies.

A crystal structure of a dimer of the antibiotic ramoplanin illustrates membrane positioning and a potential Lipid II docking interface

“…The amphipathic nature of the ramoplanin dimer clearly establishes its membrane orientation and highlights the importance of the N-acyl chain in facilitating membrane anchoring. By semisynthesis, it has been demonstrated that the ramoplanin N-acyl chain is essential for antibiotic activity; as suggested earlier, we believe this reflects a critical role for the fatty acyl chain in membrane insertion, which is necessary if ramoplanin is to interact with the membraneanchored Lipid II (19,20,24). This fatty acyl modification is conserved between ramoplanins A1-A3, ramoplanose, and the enduracidins A and B, underscoring its importance.…”

“…The structure provides a high-resolution view of the ramoplanin dimer and illustrates a potential means by which ramoplanin interacts with bacterial target membranes. Together with recent structure-activity studies, it also suggests a mechanism by which ramoplanin recognizes its Lipid II ligand (10,12,15,(19)(20)(21)(22)(23)(24)(25).…”

“…Semisynthetic modification, total synthesis, and functional studies of ramoplanin have allowed various investigators to evaluate the contributions of individual amino acids toward the molecule's activity (10,12,15,(19)(20)(21)(22)(23)(24)(25). The results presented here allow us to rationalize many of these observations in terms of the structure.…”

Antibiotic discovery in the twenty-first century: current trends and future perspectives

“…Many derivatives showed an antimicrobial activity similar to that of the precursor, and a significantly improved local tolerability. 61 The recently described, fully synthetic lactam analog of ramoplanin showed the same biological activity as the natural product. Moreover, a set of alanine analogs, obtained by total synthesis, has provided insights into the importance of individual amino-acid residues on ramoplanin activity.…”

Pharmacological Properties of NAI-603, a Well-Tolerated Semisynthetic Derivative of Ramoplanin

“…Because of ramoplanin's favorable antibacterial properties, efforts have been made to generate ramoplanin analogs by total synthesis (11)(12)(13)(14) or by semisynthesis of the natural compound (15). Alanine scanning experiments demonstrated that hydroxyphenylglycine in position 11 and the ornithine in position 10 are essential for the antibiotic activity (11,13), together with the presence of the fatty acid (11).…”