The Vancomycin Group of Antibiotics and the Fight against Resistant Bacteria

Williams, Dudley H.; Bardsley, Ben

doi:10.1002/(sici)1521-3773(19990503)38:9<1172::aid-anie1172>3.0.co;2-c

Cited by 489 publications

(367 citation statements)

References 82 publications

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“…4 Less appreciated is that the clinical formulation of vancomycin is exclusively the (P) isomer of the molecule (Figure 2, Compound 1); the highly-strained cyclophane (M) isomer remains undetected. 5 This exclusivity also extends to the axial chirality shown by both biaryl ethers. The increasing instances of vancomycin resistance have hence necessitated the need for alternative treatments, though it is clear that this naturally-produced atropisomer has played a crucial role in the progression of antibiotic drugs, and has acted as a safeguard from penicillinresistant microbes for decades.…”

Section: Natural Atropisomerism In Medicinal Chemistrymentioning

confidence: 73%

A twist of nature – the significance of atropisomers in biological systems

2015

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. (2015). A twist of nature-the significance of atropisomers in biological systems. Natural Product Reports: a journal of current development in bioorganic chemistry, 32 (11), 1562-1583. A twist of nature-the significance of atropisomers in biological systems AbstractRecently identified natural atropisomeric compounds with potential medicinal applications are presented. The ability of natural receptors to possess differential binding between atropisomers is an important factor when considering active and inactive atropisomeric drugs, and has required the development of new techniques for atropselective synthesis of desired targets. Advances in this field therefore have significant relevance to modern pharmaceutical and medicinal chemistry. The atropisomeric natural products discussed include hibarimicinone, flavomannins, talaromannins, viriditoxin, rugulotrosin A, abyssomicin C, marinopyrroles, dixiamycins, streptorubin B, ustiloxins A-F, haouamine A, bisnicalaterines, and tedarene B, all of which show significant potential as leads in antibiotic, antiviral and anticancer studies. The importance for the development of common practices regarding atropisomer recognition and classification is also emphasized. AbstractRecently identified natural atropisomeric compounds with potential medicinal applications are presented. The ability of natural receptors to possess differential binding between atropisomers is an important factor when considering active and inactive atropisomeric drugs, and has required the development of new techniques for atropselective synthesis of desired targets. Advances in this field therefore have significant relevance to modern pharmaceutical and medicinal chemistry. The atropisomeric natural products discussed include hibarimicinone, flavomannins, talaromannins, viriditoxin, rugulotrosin A, abyssomicin C, marinopyrroles, dixiamycins, streptorubin B, ustiloxins A-F, haouamine A, bisnicalaterines, and tedarene B, all of which show significant potential as leads in antibiotic, antiviral and anticancer studies. The importance for the development of common practices regarding atropisomer recognition and classification is also emphasized.

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Section: Natural Atropisomerism In Medicinal Chemistrymentioning

confidence: 73%

A twist of nature – the significance of atropisomers in biological systems

2015

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“…Exceptions are: (1) Small residue (S, G, A), (2) Positively Charged Residue (K, H, R), (3) Majority Hydrophobic (L, V; also S and G), (4) Majority Small (S, A; also V). b Percentage of residues matching to the overall consensus rule, based upon similarity.…”

Section: Identification Of a Common Motif In P450smentioning

confidence: 99%

“…2, 3). These glycopeptide antibiotics have had great clinical success in treating Gram-positive bacterial infections that are resistant to other classes of antibiotics and function through blocking cell wall biosynthesis via complex formation with the cell wall precursor peptidoglycan peptidyl units terminating in -Lys-D-Ala-D-Ala (2,3). The biosynthesis of the vancomycin peptide requires the incorporation of two amino acid residues derived from ␤-R-hydroxytyrosine.…”

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Structural Characterization of OxyD, a Cytochrome P450 Involved in β-Hydroxytyrosine Formation in Vancomycin Biosynthesis

Cryle

Meinhart

Schlichting

2010

Journal of Biological Chemistry

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The cytochrome P450 OxyD from the balhimycin glycopeptide antibiotic biosynthetic operon of Amycolatopsis mediterranei is involved in the biosynthesis of the modified amino acid ␤-R-hydroxytyrosine, an essential precursor for biosynthesis of the vancomycin-type aglycone. OxyD binds the substrate tyrosine not free in solution, but rather covalently linked to the carrier protein (CP) domain of the non-ribosomal peptide synthase BpsD, exhibiting micromolar binding affinity to a tyrosineloaded carrier protein construct. The crystal structure of OxyD was determined to 2.1-Å resolution, revealing a potential binding site for the carrier protein-bound substrate in a different orientation to that seen with the acyl carrier protein-bound P450 BioI Hydroxylated amino acid residues are widely utilized in nature as precursors for complex natural products (see Fig. 1). The oxidative modification of amino acids at the ␤-position is a process that occurs in many different classes of medicinally important biomolecules, including the vancomycin-type antibiotics (reviewed in Refs. 2, 3). These glycopeptide antibiotics have had great clinical success in treating Gram-positive bacterial infections that are resistant to other classes of antibiotics and function through blocking cell wall biosynthesis via complex formation with the cell wall precursor peptidoglycan peptidyl units terminating in -Lys-D-Ala-D-Ala (2, 3). The biosynthesis of the vancomycin peptide requires the incorporation of two amino acid residues derived from ␤-R-hydroxytyrosine. Another group of medicinally important molecules that contain hydroxylated amino acid residues is the aminocoumarincontaining angucycline family of antibiotic compounds, which include coumermycin A, clorobiocin, and simocyclinone and act upon bacterial DNA gyrase. ␤-R-Hydroxytyrosine is an essential precursor in the biosynthesis of these types of antibiotics, where it is needed for the formation of both the A (Fig. 1, blue) and B (Fig. 1, red) rings in the aminocoumarin core. Further examples of the incorporation of hydroxylated amino acids into the biosyntheses of medicinally important compounds can be found in the biosyntheses of the nikkomycin-type antibiotics, zorbamycin and echinomycin ( Fig. 1) (4 -7).Despite the large structural difference in the compounds highlighted above and the difference in the biosyntheses of the compounds overall, the formation of the ␤-hydroxyamino acid precursors follows a conserved route. This involves the oxidation of the amino acid by a member of the cytochrome P450 (P450) 2 superfamily. P450s form a superfamily of heme containing monoxygenases that catalyze a vast array of biologically important transformations (8). The archetypical P450 reaction is the hydroxylation of unactivated C-H bonds, a difficult oxidation made more impressive by the ability of P450s to utilize their oxidative power both regio-and stereoselectively. Many P450s play important roles in natural product biosyntheses, where such selectivity is channeled toward the synthesis of comp...

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“…Interestingly, many glycopeptide antibiotics [vancomycin (2), eremomycin (1), ristocetin A (5), etc.] form dimeric complexes in aqueous solution [4].…”

Section: A New Series Of Glycopeptide Antibiotics Incorporating a Squmentioning

confidence: 99%

A New Series of Glycopeptide Antibiotics Incorporating a Squaric Acid Moiety

et al. 2006

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The aglycones of the antibiotics eremomycin, vancomycin and ristocetin (3, 4 and 6, respectively) were prepared by deglycosidation of the parent antibiotics with hydrogen fluoride, and complete assignation of their 1 H, 13 C and 15 N spectra was performed. The squaric acid amide esters (11ϳ14), were prepared from dimethyl squarate. The corresponding asymmetric diamides (16ϳ19, 22, 23) were also synthesized using 4-phenylbenzylamine and triglycine. The advantage of the method is the high regioselectivity and that no protecting group strategy is required. Electrospray mass spectroscopic method was elaborated for the determination of the site of substitution of the modified antibiotics. The antibacterial activity of the prepared compounds is discussed in detail.

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The Vancomycin Group of Antibiotics and the Fight against Resistant Bacteria

Cited by 489 publications

References 82 publications

A twist of nature – the significance of atropisomers in biological systems

A twist of nature – the significance of atropisomers in biological systems

Structural Characterization of OxyD, a Cytochrome P450 Involved in β-Hydroxytyrosine Formation in Vancomycin Biosynthesis

A New Series of Glycopeptide Antibiotics Incorporating a Squaric Acid Moiety

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