Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Peptide containing doai
Reexamination Certificate
2000-03-31
2003-02-11
Russel, Jeffrey E. (Department: 1653)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Peptide containing doai
C530S322000, C530S343000
Reexamination Certificate
active
06518243
ABSTRACT:
BACKGROUND OF THE INVENTION
1. Field of the Invention
The present invention relates to glycopeptide compounds having antibiotic activity, and methods of making glycopeptide compounds having antibiotic activity.
2. Background of the Invention
Glycopeptide antibiotics are characterized by having at least one saccharide group chemically bonded to a rigid peptide structure having a cavity or cleft which acts as a binding site for the substrate used in bacterial cell wall synthesis. The glycopeptide antibiotics are further categorized into various subclasses depending on the identity and interconnections of the amino acids comprising the peptide backbone and the number and substitution pattern of the sugar residues in the molecule. The glycopeptide antibiotics are generally active against Gram-positive bacteria but relatively ineffective against Gram-negative bacteria. Most notable among the glycopeptide antibiotics is vancomycin. Vancomycin is produced by
Amycolatopsis orientalis,
and is often referred to as “the drug of last resort” because it is effective against most multi-drug-resistant gram positive bacteria. However, in recent years, vancomycin-resistant strains of some bacteria have emerged.
The structural formula of vancomycin is shown below and is characterized by a disaccharide moiety covalently linked to a heptapeptide structure. The structure of vancomycin places it in a class of molecules referred to as the “dalbaheptides.” [Malabarba A., et al. (1997a)]. Dalbaheptides in general are characterized by the presence of seven amino acids linked together by peptide bonds and held in a rigid conformation by cross-links through the aromatic substituent groups of at least five of the amino acid residues. In the heptapeptide structure of vancomycin, which is commonly referred to as the “aglycone” of vancomycin, the aromatic side-chains of amino acids 2, 4, and 6 are fused together through ether linkages. The aromatic side-chains of amino acids 5 and 7 are joined via a carbon-carbon bond. Amino acids 1 and 3 are N-methyl leucine and asparagine, respectively. Other naturally-occurring glycopeptide antibiotics are similar to vancomycin in that they have the same amino acids 1 through 7 forming the peptide binding pocket and a glucose residue linked to the aromatic substituent on amino acid 4 through formation of a bond with a phenolic hydroxyl group. The glucose residue, in turn, is linked through its vicinal hydroxyl position to a unique amino sugar, L-vancosamine. Some glycopeptide antibiotics similar to vancomycin contain additional glycosidic groups attached to other positions on the peptide (e.g. chloroeremomycin). Still other glycopeptide antibiotics such as &bgr;-avoparcin are similar to vancomycin in that they contain the same amino acids at all positions except positions one and three. &bgr;-avoparcin, for example, contains an amino acid containing an aromatic side chain in place of the asparagine at position three and does not contain N-methyl leucine at position one. &bgr;-avoparcin contains glycosidic groups at amino acid 4 and at other positions on the peptide core.
Vancomycin, chloroeremomycin and &bgr;-avoparcin have the structures as shown below:
Eremomycin has the structure of chloroeremomycin except that the chlorine substituent on the aromatic group attached to amino acid 6 is not present in eremomycin.
The anti-microbial activity of the naturally occurring glycopeptide antibiotics is believed to be due to their ability to interfere with biosynthesis of the bacterial cell wall, evidently by binding to dipeptide termini of uncross-linked peptidoglycan and/or the disaccharide precursor of peptidoglycan. [Nagarajan R. (1993)]. NMR evidence has shown that the heptapeptide chain of vancomycin forms a number of hydrogen bonds with D-alanyl-D-alanine, the dipeptide that is at the terminus of the peptide chain attached to the N-acetylmuramic acid unit that is incorporated into peptidoglycan. [See, e.g., Prowse W., et al. (1995); Pierce C., et al. (1995); Williams D. et al. (1998)]. The interaction of vancomycin with peptidoglycan precursors apparently inhibits or prevents the subsequent transglycosylation and/or transpeptidation steps of cell wall assembly. Supporting this mode of action is the fact that vancomycin-resistant strains of bacteria are found to produce a pentapeptide precursor terminating in a D-alanyl-D-lactate sequence. It is hypothesized that the reduced effectiveness of vancomycin against resistant strains is due to reduced hydrogen bonding interactions between the drug and the D-alanyl-D-lactate substrate (and possibly repulsive interactions as well). The affinity of vancomycin for D-alanyl-D-lactate is estimated to be 2-3 orders of magnitude (4.1 kcal/mol) less than for D-alanyl-D-alanine. [Walsh C (1993)].
The sugar residues of vancomycin and other glycopeptide antibiotics have been shown to affect biological activities. Structural changes in the sugar residues can produce significant changes in antibiotic activity. [Malabarba (1997); Nagarajan, R. (1993)]. It has been proposed that the sugar residues on the glycopeptide antibiotics may enhance the avidity of these molecules for surface-bound peptide ligands. At least two different mechanisms for enhancing avidity have been proposed. [Kannan (1998); Gerhard (1993); Allen (1997)].
For example, it has been proposed that the biological activity of vancomycin, along with that of many other glycopeptide antibiotics, is enhanced by dimerization [Williams D., et al. (1993); Gerhard U., et al., (1993)] facilitated by the saccharide groups on the convex surface of the molecules. Structural evidence for dimerization of several different glycopeptides has been obtained from both NMR and crystallographic studies. It has been found that there are significant differences in the stability of the dimers formed in solution by different glycopeptide antibiotics. [MacKay (1994)]. Dimerization is thought to influence activity by increasing the avidity of the glycopeptides for surface-bound D-ala-D-ala peptide ligands [Williams, (1998)]. It is proposed that the differences in the dimerization constants, due to different interactions between saccharide groups, may account at least partially for the differences in biological activity of different glycopeptide antibiotics which otherwise have very similar peptide binding pockets and also have similar affinities for the natural D-ala-D-ala substrate. [Williams (1998)].
A second mechanism for enhancing activity has been proposed for the naturally occurring glycopeptide antibiotic teicoplanin and various semi-synthetic glycopeptides containing hydrophobic substituents on at least one of the saccharide units. It is suggested that hydrophobic substituents (a C2 N-acyl group in the case of teicoplanin) interact with the bacterial membrane, thus “anchoring” hydrophobically substituted glycopeptides at the membrane surface. [Beauregard (1995)]. Membrane anchoring is proposed to enhance activity by localizing the glycopeptide antibiotic to the membrane where the Lipid II substrates that are the precursors of peptidoglycan are found. The glycopeptide antibiotics then bind to the dipeptide termini of these precursors and prevent transglycosylation and/or transpeptidation.
It should be noted that teicoplanin is active against some vancomycin resistant strains. Furthermore, the attachment of hydrophobic substituents to the vancomycin carbohydrate moiety confers activity against these and other vancomycin-resistant bacterial strains. [Nagarajan (1991)]. It has been speculated that the lipophilic groups on the saccharides, in locating the antibiotic at the cell surface, help overcome the decreased binding affinity for D-ala-D-lac in vancomycin resistant microorganisms.
It has generally been assumed that peptide binding is essential for biological activity. In fact, it had been shown that if the peptide core of vancomycin is damaged by removing the N-methyl leucine (
Kahne Daniel
Walker Suzanne
Kenyon & Kenyon
Russel Jeffrey E.
Trustees of Princeton University
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