In vitro activity of LY264826, a new glycopeptide antibiotic, against gram-positive bacteria isolated from patients with cancer

Rolston, Kenneth V. I.; Nguyen, Hieu; Messer, Mark

doi:10.1128/aac.34.11.2137

Cited by 18 publications

(7 citation statements)

References 10 publications

(6 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…However, clinical trials have not been completed to establish the toxicity of the new derivatives. LY264826, a novel glycopeptide, showed promising activity that was at least comparable to those of teicoplanin and vancomycin (46,263). The genetic and biochemical mechanisms responsible for resistance to glycopeptides in CNS are not clear.…”

Section: Conventional Methodsmentioning

confidence: 99%

Update on clinical significance of coagulase-negative staphylococci

1994

View full text Add to dashboard Cite

The clinical significance of coagulase-negative Staphylococcus species (CNS) continues to increase as strategies in medical practice lead to more invasive procedures. Hospitalized patients that are immunocompromised and/or suffering from chronic diseases are the most vulnerable to infection. Since CNS are widespread on the human body and are capable of producing very large populations, distinguishing the etiologic agent(s) from contaminating flora is a serious challenge. For this reason, culture identification should proceed to the species and strain levels. A much stronger case can be made for the identification of a CNS etiologic agent if the same strain is repeatedly isolated from a series of specimens as opposed to the isolation of different strains of one or more species. Strain identity initially can be based on colony morphology, and then one or more molecular approaches can be used to gain information on the genotype. Many of the CNS species are commonly resistant to antibiotics that are being indicated for staphylococcal infections, with the exception of vancomycin. The widespread use of antibiotics in hospitals has provided a reservoir of antibiotic-resistant genes. The main focus on mechanisms of pathogenesis has been with foreign body infections and the role of specific adhesins and slime produced by Staphylococcus epidermidis. Slime can reduce the immune response and opsonophagocytosis, thereby interfering with host defense mechanisms. As we become more aware of the various strategies used by CNS, we will be in a better position to compromise their defense mechanisms and improve treatment.

show abstract

Section: Conventional Methodsmentioning

confidence: 99%

Update on clinical significance of coagulase-negative staphylococci

1994

View full text Add to dashboard Cite

show abstract

“…LY264826 (A82846B) is a glycopeptide antibiotic with a structure similar to that of vancomycin but containing an additional amino sugar (4-epivancosamine) (28). The antibacterial activity of LY264826 is, on average, four-to eightfold greater than that of vancomycin against several gram-positive species (27,31,39). Despite the difference in activities, LY264826 and vancomycin share similar affinities for binding the D-Ala-D-Ala-containing tripeptide ligand N,NЈ-diacetyl-L-Lys-D-Ala-D-Ala (23), and both agents inhibit the transglycosylation reaction in peptidoglycan biosynthesis (1).…”

mentioning

confidence: 99%

Molecular interactions of a semisynthetic glycopeptide antibiotic with D-alanyl-D-alanine and D-alanyl-D-lactate residues

Allen

LeTourneau

Hobbs

1997

Antimicrob Agents Chemother

View full text Add to dashboard Cite

LY191145 is an N-alkylated glycopeptide antibiotic (the p-chlorobenzyl derivative of LY264826) with activity against vancomycin-susceptible and -resistant bacteria. Similar to vancomycin, LY191145 inhibited polymerization of peptidoglycan when muramyl pentapeptide served as a substrate but not when muramyl tetrapeptide was used, signifying a substrate-dependent mechanism of inhibition. Examination of ligand binding affinities for LY191145 and the effects of this agent on R39 D,D-carboxypeptidase action showed that, similar to vancomycin, LY191145 had an 800-fold greater affinity for N,N'-diacetyl-L-Lys-D-Ala-D-Ala than for N,N'-diacetyl-L-Lys-D-Ala-D-Lac. The antibacterial activity of LY191145 was antagonized by N,N'-diacetyl-L-Lys-D-Ala-D-Ala, but the molar excess required for complete suppression exceeded that needed to suppress inhibition by vancomycin. LY191145 is strongly dimerized and the p-chlorobenzyl side chain facilitates interactions with bacterial membranes. These findings are consistent with a mechanism of inhibition where interactions between antibiotic and D-Ala-D-Ala or D-Ala-D-Lac residues depend on intramolecular effects occurring at the subcellular target site.

show abstract

“…1) (29). The antibacterial activity of LY264826 is approximately four-to eightfold greater than that of vancomycin (24,27,35). Several derivatives of LY264826 with N-substituted alkyl hydrophobic side chains on the 4-epi-vancosamine of the disaccharide sugar and exquisite antibacterial activities against both vancomycin-susceptible and -resistant bacteria have been described (12,25,27,28,34).…”

mentioning

confidence: 99%

Hexapeptide Derivatives of Glycopeptide Antibiotics: Tools for Mechanism of Action Studies

Allen

Letourneau

Hobbs

et al. 2002

Antimicrob Agents Chemother

View full text Add to dashboard Cite

Binding to D-Ala-D-Ala residues can lead to inhibition of transglycosylation and/or transpeptidation; these interactions in turn lead to bacterial growth inhibition (33). LY264826 (A82846B, chloroeremomycin, or chloroorienticin A) differs from vancomycin in having a 4-epi-vancosamine sugar substituted for vancosamine in the disaccharide attached at residue 4 and an additional 4-epi-vancosamine attached at residue 6 of the linear heptapeptide ( Fig. 1) (29). The antibacterial activity of LY264826 is approximately four-to eightfold greater than that of vancomycin (24,27,35). Several derivatives of LY264826 with N-substituted alkyl hydrophobic side chains on the 4-epi-vancosamine of the disaccharide sugar and exquisite antibacterial activities against both vancomycin-susceptible and -resistant bacteria have been described (12,25,27,28,34).Despite differences in antibacterial activities, vancomycin, LY264826, and the hydrophobic side chain derivatives of LY264826 and its derivatives (as well as some other members of the glycopeptide class) have a strong tendency to selfassociate and form homodimers (2,3,15,18). The extent of dimerization of LY264826 is approximately 2 orders of magnitude greater than that of vancomycin (2,15,22). The Nsubstituted derivatives of LY264826 are even more strongly dimerized, with the extent of dimerization apparently determined by the nature of the side chain (3). The N-substituted derivatives also demonstrate a greater tendency to interact with bacterial membranes, a process that could serve to anchor these agents at the in vivo target site (2,3,5,6,11,37). Our studies (3) revealed a relatively high degree of correlation between the extent of dimerization of glycopeptide antibiotics and antibacterial activity and a very high degree of correlation between antibacterial activity and the concentration of a DAla-D-Ala-containing tripeptide ligand needed in the growth medium to antagonize antibacterial activity. The antagonism experiments are particularly pertinent to the mechanisms of action of these glycopeptides because the results imply that growth inhibition is accompanied by stronger interactions with D-Ala-D-Ala-containing cell wall intermediates at the in vivo target site than with the D-Ala-D-Ala-containing tripeptide ligand in solution. The combined effect of dimerization and membrane anchoring can lead to cooperative interactions that facilitate strong intramolecular effects at the target site that can fully account for the enhanced antibacterial activities. These kinds of interactions are not predicted by estimating association constants in free solution. However, the contribution of intramolecular effects to the binding of glycopeptide antibiotics to D-Ala-D-Ala and D-Ala-D-Lac residues at the bacterial surface has been demonstrated by nuclear magnetic resonance and surface plasmon resonance techniques with a variety of model systems, namely, phosphatidylcholine vesicles * Corresponding author. Present address: 1481 E. 77th St., Indianapolis, IN 46240.

show abstract

In vitro activity of LY264826, a new glycopeptide antibiotic, against gram-positive bacteria isolated from patients with cancer

Abstract: The in vitro activity of LY264826, a novel glycopeptide antibiotic produced by Amycolatopsis orientalis, was compared with those of vancomycin, teicoplanin, and oxacillin against 311

Cited by 18 publications

References 10 publications

Update on clinical significance of coagulase-negative staphylococci

Update on clinical significance of coagulase-negative staphylococci

Molecular interactions of a semisynthetic glycopeptide antibiotic with D-alanyl-D-alanine and D-alanyl-D-lactate residues

Hexapeptide Derivatives of Glycopeptide Antibiotics: Tools for Mechanism of Action Studies

Contact Info

Product

Resources

About