Chemistry and biology of the ramoplanin family of peptide antibiotics

Abstract

The peptide antibiotic ramoplanin factor A2 is a promising clinical candidate for treatment of Gram-positive bacterial infections that are resistant to antibiotics such as glycopeptides, macrolides, and penicillins. Since its discovery in 1984, no clinical or laboratory-generated resistance to this antibiotic has been reported. The mechanism of action of ramoplanin involves sequestration of peptidoglycan biosynthesis Lipid intermediates, thus physically occluding these substrates from proper utilization by the late-stage peptidoglycan biosynthesis enzymes MurG and the transglycosylases (TGases). Ramoplanin is structurally related to two cell wall active lipodepsipeptide antibiotics, janiemycin, and enduracidin, and is functionally related to members of the lantibiotic class of antimicrobial peptides (mersacidin, actagardine, nisin, and epidermin) and glycopeptide antibiotics (vancomycin and teicoplanin). Peptidomimetic chemotherapeutics derived from the ramoplanin sequence may find future use as antibiotics against vancomycin-resistant Enterococcus faecium (VRE), methicillin-resistant Staphylococcus aureus (MRSA), and related pathogens. Here we review the chemistry and biology of the ramoplanins including its discovery, structure elucidation, biosynthesis, antimicrobial activity, mechanism of action, and total synthesis.

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

“…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).…”

“…At least three forms are known, A1, A2, and A3; these forms differ in their acyl chain substituents, but possess essentially identical antibiotic activities. Ramoplanins are structurally and functionally related to ramoplanose, which is produced by Actinoplanes strain U.K.-71,903 and which differs from factor A2 by one mannose unit (7), and to enduracidin A and B, which are produced by Streptomyces fungicidicus B5477 (8)(9)(10). This paper focuses on the ramoplanin A2 isomer, the most abundant among the A1-A3 forms; for simplicity's sake, we refer to this isomer as ramoplanin for the remainder of the manuscript.…”

“…Lipid II sequestration precludes formation of the mature, fully cross-linked peptidoglycan, leading to a mechanically weakened cell wall and bacterial death from osmotic lysis (11)(12)(13)(14). Thus, like the glycopeptide antibiotics, ramoplanin inhibits cell wall biosynthesis, but the molecular underpinnings are distinct, since the binding epitopes on Lipid II that are recognized by the two types of antibiotics are largely non-overlapping (3,4,10,15,16). This differential targeting likely explains ramoplanin's excellent activity against vancomycin-resistant microorganisms.…”

An asparagine oxygenase (AsnO) and a 3-hydroxyasparaginyl phosphotransferase (HasP) are involved in the biosynthesis of calcium-dependent lipopeptide antibiotics

“…CDA variants which contain either (2R,3S)-3-hydroxyasparagine (3-OHAsn) or (2R,3S)-3-phosphohydroxyasparagine (3-OPAsn) at position 9 are also known. Whilst 3-OHAsn is common to a number of peptide antibiotics, including A54145 (Fukuda et al, 1990;Miao et al, 2006), katanosin B (Kato et al, 1988) and ramoplanin (Walker et al, 2005;McCafferty et al, 2002), 3-phosphohydroxyasparagine has not been found elsewhere in nature, to date.…”

“…Indeed the subsequent processing of the amino acid b-hydroxyl groups by further oxidation (Chen et al, 2002), glycosylation (Lu et al, 2004), macrolactonization (Kato et al, 1988;Walker et al, 2005;McCafferty et al, 2002), methylation (Miao et al, 2006) or in the case of CDA, phosphorylation, serves to increase the structural diversity of nonribosomal peptides and related products, resulting in a wide range of biological activities. Of the many bhydroxylated amino acids and derivatives found in nonribosomal peptides, some arise as a result of the oxidation of free amino acids prior to peptide assembly (Yin & Zabriskie, 2004;Ju et al, 2004;Haltli et al, 2005).…”