Mannopeptimycins, Novel Antibacterial Glycopeptides from Streptomyces hygroscopicus, LL-AC98

Abstract

A series of novel antibiotics with activity against methicillin-resistant staphylococci and vancomycin-resistant enterococci has been purified, and their structures have been characterized using spectroscopic analyses and chemical conversions. These antibiotics, designated mannopeptimycins alpha-epsilon (1-5), are glycosylated cyclic hexapeptides containing two stereoisomers of an unprecedented amino acid, alpha-amino-beta-[4'-(2'-iminoimidazolidinyl)]-beta-hydroxypropionic acid (Aiha), as a distinguishing feature. The cyclic peptide core of these antibiotics is attached to a mannosyl monosaccharide moiety in 2 and to mannosyl monosaccharide and disaccharide moieties in 1, 3, 4, and 5. The presence and position of an isovaleryl group in the terminal mannose (Man-B) in 3-5 are critical for retaining antibacterial potency.

Bioactive Microbial Metabolites

“…The original isolation of the antibiotic LL-AC98 happened in 1970, but its original new structure and possible practical usefulness has been discovered only recently. This compound, renamed as mannopeptimycin [29] is an interesting cyclopeptide containing mannose side chains and imidazole moiety. This exciting molecule has a relatively new type of structure and promising antimicrobial properties with significant activity against numerous resistant bacteria [30].…”

Comparative In Vitro Activities of AC98-6446, a Novel Semisynthetic Glycopeptide Derivative of the Natural Product Mannopeptimycin α, and Other Antimicrobial Agents against Gram-Positive Clinical Isolates

“…However, because of the increasing problem of resistance among grampositive organisms, a retrospective reevaluation of previous natural-product leads was undertaken. The AC98 complex was separated into its individual components and fully characterized (14). The individual components of the complex are referred to as mannopeptimycin ␣ through ε.…”

Genome Mining of EndophyticStreptomyces wadayamensisReveals High Antibiotic Production Capability

“…38 Its activity was also confirmed against methicillin resistant staphylococci and vancomycin resistance enterococci. 39 The biosynthetic pathway for mannopeptimycins was described by Margavey et al 40 in 2006. Looking closely and performing blast and protein function comparison, it is possible to verify that the main genes mppA and mppB responsible for the hexapeptide core are 100% identical in S. wadayamensis A23 (genes 23 and 24 in Figure 10A) and S. hygroscopicus NRRL 30439, revealing similar operon type organization ( Figure 10B).…”