The Structure and Mode of Action of Glycopeptide Antibiotics of the Vancomycin Group

1984 ◽  
Vol 38 (1) ◽  
pp. 339-357 ◽  
Author(s):  
J C J Barna ◽  
D H Williams
2017 ◽  
Vol 121 (16) ◽  
pp. 3925-3932 ◽  
Author(s):  
Manmilan Singh ◽  
James Chang ◽  
Lauryn Coffman ◽  
Sung Joon Kim

2017 ◽  
Vol 199 (15) ◽  
Author(s):  
James D. Chang ◽  
Erin E. Foster ◽  
Aanchal N. Thadani ◽  
Alejandro J. Ramirez ◽  
Sung Joon Kim

ABSTRACT Oritavancin is a lipoglycopeptide antibiotic that exhibits potent activities against vancomycin-resistant Gram-positive pathogens. Oritavancin differs from vancomycin by a hydrophobic side chain attached to the drug disaccharide, which forms a secondary binding site to enable oritavancin binding to the cross-linked peptidoglycan in the cell wall. The mode of action of secondary binding site was investigated by measuring the changes in the peptidoglycan composition of Staphylococcus aureus grown in the presence of desleucyl-oritavancin at subinhibitory concentration using liquid chromatography-mass spectrometry (LC-MS). Desleucyl-oritavancin is an Edman degradation product of oritavancin that exhibits potent antibacterial activities despite the damaged d-Ala–d-Ala binding site due to its functional secondary binding site. Accurate quantitative peptidoglycan composition analysis based on 83 muropeptide ions determined that cell walls of S. aureus grown in the presence of desleucyl-oritavancin showed a reduction of peptidoglycan cross-linking, increased muropeptides with a tetrapeptide-stem structure, decreased O-acetylation of MurNAc, and increased N-deacetylation of GlcNAc. The changes in peptidoglycan composition suggest that desleucyl-oritavancin targets the peptidoglycan template to induce cell wall disorder and interferes with cell wall maturation. IMPORTANCE Oritavancin is a lipoglycopeptide antibiotic with a secondary binding site that targets the cross-linked peptidoglycan bridge structure in the cell wall. Even after the loss of its primary d-Ala–d-Ala binding site through Edman degradation, desleucyl-oritavancin exhibits potent antimicrobial activities through its still-functioning secondary binding site. In this study, we characterized the mode of action for desleucyl-oritavancin's secondary binding site using LC-MS. Peptidoglycan composition analysis of desleucyl-oritavancin-treated S. aureus was performed by determining the relative abundances of 83 muropeptide ions matched from a precalculated library through integrating extracted ion chromatograms. Our work highlights the use of quantitative peptidoglycan composition analysis by LC-MS to provide insights into the mode of action of glycopeptide antibiotics.


Structure ◽  
1994 ◽  
Vol 2 (8) ◽  
pp. 747-754 ◽  
Author(s):  
Patrick Groves ◽  
Mark S Searle ◽  
Joel P Mackay ◽  
Dudley H Williams

2020 ◽  

Background: Infective endocarditis (IE) is a relatively rare disease but with significant rates of morbidity and mortality. The goal of IE treatment is to eradicate the foci of infection, including antimicrobial therapy with or without surgery. The decision on the selection of an empirical therapy regimen is diverse and based on patient characteristics. Vancomycin and teicoplanin are bacteriostatic glycopeptide antibiotics used for the treatment of methicillin-resistant Staphylococcus aureus (MRSA) infections, including MRSA-IE, and patients allergic to penicillin who are infected with methicillin-sensitive Staphylococcus aureus. Objective: The current study aimed to compare the efficacy and adverse effects of vancomycin and teicoplanin in the treatment of patients with MRSA-IE. Materials and Methods: This parallel, randomized, and controlled trial study was carried out on the efficacy and safety of teicoplanin versus vancomycin in the treatment of MRSA endocarditis within August 2012 and April 2017. The present study recruited adult patients with a definite or possible diagnosis of IE based on the Modified Duke Criteria. A central computer-generated random number list was used to allocate the patients (1:1) to the treatment with teicoplanin or vancomycin. Vancomycin was intravenously administered at a dose of 30 mg/kg/day in two doses. Teicoplanin was administered at a loading dose of 6-12 mg/kg every 12 h in four doses and then continued once a day. Results: Out of 86 patients screened with suspected IE, 66 patients were randomly assigned to the vancomycin (n=33) and teicoplanin (n=33) groups. The mean age values of the study subjects were 41±11.8 and 39±13.1 years in the vancomycin and teicoplanin groups, respectively. In addition, 27 patients (81.8%) in the vancomycin group met the criteria for microbiological cure, compared to 25 subjects (89.3%) in the teicoplanin group. In this regard, the observed difference was not statistically significant (P=0.41). Moreover, 26 (78.8%) and 23 (82.1%) patients in the vancomycin and teicoplanin groups achieved clinical cure, respectively (P=0.97). Overall, the patients in the vancomycin group experienced more adverse events in comparison to those of the teicoplanin group (P=0.04). The rate of acute kidney injury over time, especially in the first week of therapy, was higher in the vancomycin group than that reported for the teicoplanin group (P=0.05). Six and four patients in the vancomycin and teicoplanin groups required dialysis, respectively. The use of dialysis was not different between the two groups (P=0.88). Seven (21.3%) and five (17.9%) patients in the vancomycin and teicoplanin groups died, respectively, which was not statistically different between the two groups (P=0.74). Conclusions: It was concluded that the administration of vancomycin or teicoplanin does not significantly change the outcome of patients undergoing empirical treatment for MRSA-IE. This finding indicates the patients are similar in clinical outcomes and mortalities despite some adverse effects, such as skin rashes; therefore, teicoplanin can be considered a treatment choice for these diseases.


Author(s):  
E. A. Elfont ◽  
R. B. Tobin ◽  
D. G. Colton ◽  
M. A. Mehlman

Summary5,-5'-diphenyl-2-thiohydantoin (DPTH) is an effective inhibitor of thyroxine (T4) stimulation of α-glycerophosphate dehydrogenase in rat liver mitochondria. Because this finding indicated a possible tool for future study of the mode of action of thyroxine, the ultrastructural and biochemical effects of DPTH and/or thyroxine on rat liver mere investigated.Rats were fed either standard or DPTH (0.06%) diet for 30 days before T4 (250 ug/kg/day) was injected. Injection of T4 occurred daily for 10 days prior to sacrifice. After removal of the liver and kidneys, part of the tissue was frozen at -50°C for later biocheailcal analyses, while the rest was prefixed in buffered 3.5X glutaraldehyde (390 mOs) and post-fixed in buffered 1Z OsO4 (376 mOs). Tissues were embedded in Araldlte 502 and the sections examined in a Zeiss EM 9S.Hepatocytes from hyperthyroid rats (Fig. 2) demonstrated enlarged and more numerous mitochondria than those of controls (Fig. 1). Glycogen was almost totally absent from the cytoplasm of the T4-treated rats.


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