Vancomycin modification

Resistance to vancomycin in enterococci is due to modification of the D-Ala-D-Ala binding site of the peptidoglycan building block in which the terminal D-Ala is replaced by D-lactate. This results in the loss of a critical hydrogen bond that facilitates high-affinity binding of vancomycin to its target and loss of activity. This mechanism is also present in vancomycin-resistant S aureus strains (MIC s32. ug/mL), which have acquired the enterococcal resistance determinants. The mechanism for reduced vancomycin susceptibility of vancomycin-intermediate strains (MICs = 8-16 g/mL) is not known. 

Vancomycin, a natural product that was first approved in 1955, is still the prototype for structural variations with the same mechanism of action the binding to the terminal L-Lys-D-Ala-D-Ala tripeptide in Gram-positive cell wall biosynthesis. The compounds below are semi-synthetic modifications of the same basic structural class (glycopeptides) as the prototype vancomycin, thus following in the chemical footsteps of the (1-lactams currently, there are three semi-synthetic glycopeptides, oritavancin 39, telavancin 40 and dalba-vancin 41, in late stage clinical development. 

Scheme 2-9. Semisynthetic modifications of vancomycin-type glycopeptide antibiotics, (a) Alterations and modifications of amino acids, (b) Attachment of molecules to the amino groups, to the carboxy groups, and to phenolic carbohydrate functionalities. Similar modifications have been performed for antibiotics of the teicoplanin-type.

M. Nieto and H. R. Perkins, Modifications of the acyl-D-alanyl-D-alanine terminus affecting complex formation with vancomycin, Biochem. J. 123 (1971), 789. 

Others Sequestration Immunity Proteins Target Modification Altered Metabohc Pathway Target Overexpression P-Lactams, Enediynes Bleomycin, Tetracycline Fluoroquinolones, Macrolides Vancomycin Trimethoprim... 

Vancomycin underwent spontaneous chemical modification when kept at room temperature at neutral pH in aqueous solutions containing traces of formaldehyde or acetaldehyde (110). In vitro studies on two different strains of bacteria showed that the resulting compounds had reduced antibacterial activity. 

Heck AJ, Bonnici PJ, Breukink E, Morris D, Wills M. Modification and inhibition of vancomycin group antibiotics by formaldehyde and acetaldehyde. Chemistry 2001 7(4) 910-16. 

Itoh F, Sato K, Harauchi T, Hirata M, Mizushima Y. Modification of vancomycin nephrotoxicity by other antibiotics in rats. Jpn J Antibiot 1995 48(3) 380-388. 

With the emergence of bacterial strains that are resistant to these glycopeptides, the first line of defense is often to synthetically modify the natural antibiotic. In the case of these glycopeptides, synthetic alteration of the aglycone stmcture is not practical, due to their complexity. However, the carbohydrate portion of the molecule [vancosamine(a l-2)glucose in the case of vancomycin] is readily accessible to modification. This strategy has led to new antibiotics that have potential for treatment of vancomycin-resistant strains. 

It has been observed that the incorporation of lipophilic chains into vancomycin can increase the potency of the dmg [159,160,161,162]. This is best exemplified by the observation that teicoplanin retains activity against some vancomycin-resistant bacterial strains. In one early study directed at improving the efficacy of these antibiotics, Ge et al. investigated the mechanism of action of a chloro-biphenyl derivative of vancomycin that showed activity against resistant bacteria [163]. The sulfoxide method of glycosylation was utilized to achieve the desired modification of the gluco-vancomycin precursor (O Scheme 28). 

In addition to the glycosyltransferase enzymes, the substrate specificity of the teicoplanin acyl-transferase (Atf), responsible for the installation of the fatty acid amide in teicoplanin, has been examined [168]. This enzyme appears to be tolerant to modifications in the amide chain length, carbohydrate structure and nature of the aglycone. This finding is of particular interest as it has been shown that installation of the lipid containing monosaccharide from teicoplanin onto vancomycin can restore antibiotic activity against several resistant strains [159]. 

Besides modification of the glycan, other strategies to overcome vancomycin resistance have been undertaken. Dimeric and trimeric vancomycin constructs bind the D-Ala-D-Ala peptide more tightly than vancomycin itself and have shown antibacterial activity against vancomycin resistant strains [169,170,171]. A potential inhibition pathway that acts through dimerization and membrane-anchoring is also being actively pursued [172,173]. 

Oritavancin is a semi-synthetic derivative of vancomycin, and differs from the parent compound by the presence of an additional 4-ej3z-vancosamine and a p-chlorodiphenyl side chain to the additional vancosamine. These modifications confer unusual pharmacodynamic and pharmacokinetic properties on oritavancin. Oritavancin exhibits rapid and concentration-dependent bactericidal activity against gram-positive bacteria in association with a prolonged postantibiotic efifeci... 

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