Vancomycin
Overview
Description
Vancomycin is a glycopeptide antibiotic primarily used to treat severe bacterial infections caused by Gram-positive bacteria, including methicillin-resistant Staphylococcus aureus (MRSA) and Clostridium difficile . It was first isolated from a soil sample in Borneo in 1956 and has since become a critical tool in combating antibiotic-resistant infections .
Mechanism of Action
Target of Action
Vancomycin, a glycopeptide antibiotic, primarily targets the D-alanyl-D-alanine (D-Ala-D-Ala) terminus of cell wall precursor units in bacteria . This terminal sequence plays a crucial role in bacterial cell wall synthesis . The antibiotic is particularly effective against severe bacterial infections such as MRSA (methicillin-resistant Staphylococcus aureus) infections .
Mode of Action
This compound operates by inhibiting cell wall synthesis in bacteria . It binds to the D-Ala-D-Ala terminus of cell wall precursor units, preventing their incorporation into the cell wall . This action weakens the bacterial cell wall, leading to cell lysis and death . There is also evidence that this compound alters the permeability of the cell membrane and selectively inhibits ribonucleic acid synthesis .
Biochemical Pathways
The primary biochemical pathway affected by this compound is the synthesis of the bacterial cell wall. By binding to the D-Ala-D-Ala terminus of cell wall precursor units, this compound prevents the transglycosylation step in peptidoglycan polymerization . This action disrupts the formation of the bacterial cell wall, leading to cell lysis and death .
Pharmacokinetics
In patients with normal creatinine clearance, this compound has an α-distribution phase of ∼30 min to 1 hour and a β-elimination half-life of 6–12 hours. The volume of distribution is 0.4–1 L/kg . The binding of this compound to protein has been reported to range from 10% to 50% .
Result of Action
The molecular effect of this compound’s action is the disruption of the bacterial cell wall, which leads to cell lysis and death . On a cellular level, this compound causes changes in the permeability of the cell membrane and selectively inhibits ribonucleic acid synthesis . This results in the inhibition of bacterial growth and proliferation.
Action Environment
Environmental factors can influence the action, efficacy, and stability of this compound. For instance, regional variations and climate types (temperate and monsoon climates) have been found to significantly affect the resistance rate of this compound-resistant Enterococcus faecalis . Furthermore, the physical environment in healthcare settings, such as the cleanliness of surfaces, can impact the transmission of this compound-resistant bacteria .
Biochemical Analysis
Biochemical Properties
Vancomycin acts by binding to the D-alanyl-D-alanine moieties of the NAM/NAG-peptides, preventing the incorporation of these subunits into the peptidoglycan matrix, which forms the major structural component of Gram-positive bacterial cell walls . This interaction is non-covalent and results in the inhibition of cell wall synthesis . This compound’s activity is concentration-independent, also referred to as “time-dependent,” and its clinical activity can be affected by factors such as variable tissue distribution, inoculum size, and emerging resistance .
Cellular Effects
This compound primarily targets bacterial cells, where it disrupts cell wall synthesis, leading to cell death . It has been shown to have variable effects on different types of cells. For example, it has been found to reduce cell viability by 20% to 30% with increasing concentration up from 0.2 mg/mL . It also induces oxidative stress, as indicated by a reduction in the antioxidant activity of SOD2 and an increase in the MDA level .
Molecular Mechanism
This compound exerts its effects at the molecular level by forming an intricate network of hydrogen bonds with the D-Ala-D-Ala region of Lipid II, interfering with the peptidoglycan layer maturation process . This binding prevents the incorporation of N-acetylmuramic acid (NAM) and N-acetylglucosamine (NAG)-peptide subunits into the peptidoglycan matrix .
Temporal Effects in Laboratory Settings
The pharmacokinetic profile of this compound is complex and can be characterized by either a 2- or 3-compartment pharmacokinetic profile . In patients with normal creatinine clearance, this compound has an α-distribution phase of approximately 30 minutes to 1 hour and a β-elimination half-life of 6–12 hours . Over time, the effects of this compound can change due to factors such as the development of resistance .
Dosage Effects in Animal Models
In animal models, the effects of this compound can vary with different dosages. For instance, in beagle dogs, this compound is administered intravenously at a dose rate of 20 mg/kg over a 1-hour period at 12-hour intervals . The effects of this compound in animal models can also be influenced by factors such as the animal’s health status and the presence of other medications.
Metabolic Pathways
This compound is not appreciably metabolized and is eliminated primarily via the renal route, with more than 80% to 90% recovered unchanged in urine within 24 hours after administration of a single dose . It has been suggested that this compound disrupts amino acids metabolism, fatty acids biosynthesis, energy metabolism, and lipid metabolism .
Transport and Distribution
This compound is administered intravenously and has a volume of distribution of 0.4–1 L/kg . It penetrates into most body spaces, although the concentrations obtained are variable and somewhat dependent on the degree of inflammation present .
Subcellular Localization
This compound accumulates in lysosomes of proximal tubular cells throughout 10 days of treatment . The subcellular localization of this compound in the renal cortices of rats was determined with ultrathin sections by immunogold labeling .
Preparation Methods
Vancomycin is produced through the fermentation of the bacterium Amycolatopsis orientalis . The industrial production involves several steps:
Fermentation: Amycolatopsis orientalis is cultured in a nutrient-rich medium to produce this compound.
Extraction: The antibiotic is extracted from the fermentation broth using organic solvents.
Purification: High-performance liquid chromatography (HPLC) is commonly used to purify this compound.
Chemical Reactions Analysis
Vancomycin undergoes various chemical reactions, including:
Oxidation and Reduction: These reactions can modify the functional groups on the this compound molecule, potentially altering its activity.
Substitution Reactions: Common reagents include acetonitrile and methanol, used in chromatographic methods.
Major Products: The primary product is the purified this compound, which retains its antibiotic properties.
Scientific Research Applications
Clinical Applications
FDA-Approved Indications:
Vancomycin is indicated for various infections, including:
- Clostridioides difficile-associated diarrhea
- Staphylococcal infections (including septicemia, skin and soft tissue infections)
- Endocarditis caused by enterococci and staphylococci
- Bone infections and lower respiratory tract infections
Off-Label Uses:
this compound is also utilized in several off-label scenarios:
- Catheter-related infections
- Bacterial meningitis
- Surgical prophylaxis
- Necrotizing skin and soft tissue infections
Research Findings
Recent studies have highlighted the efficacy of this compound in various clinical settings:
-
Topical Application in Surgical Site Infections:
A systematic review indicated that the local application of this compound powder significantly reduces the incidence of surgical site infections (SSIs) following joint arthroplasty. However, it was associated with an increased risk of complications such as delayed healing . -
Pediatric Applications:
Research has demonstrated this compound's immunomodulatory effects in pediatric patients with inflammatory bowel disease, suggesting its potential role beyond mere antibacterial action . -
Intrawound Use in Spine Surgery:
A meta-analysis involving 18 studies showed that intrawound application of this compound powder significantly lowers the odds of developing deep infections during spine surgeries compared to standard practices . The odds ratio for deep infections was found to be 0.23, indicating a substantial protective effect.
Data Table: Summary of this compound Applications
| Application Type | Description | Evidence Level |
|---|---|---|
| FDA-Approved Uses | Treats MRSA, endocarditis, bone infections | High |
| Off-Label Uses | Includes meningitis, surgical prophylaxis | Moderate |
| Topical Application | Reduces SSIs in joint surgeries | Systematic Review |
| Pediatric Immunomodulation | Affects TNF-alpha pathways in inflammatory conditions | Case Study |
| Intrawound Use in Spine Surgery | Lowers deep infection rates significantly | Meta-analysis |
Comparison with Similar Compounds
Vancomycin is often compared with other antibiotics, such as:
Linezolid: A synthetic oxazolidinone that inhibits protein synthesis.
Daptomycin: A lipopeptide that disrupts cell membrane function.
Tigecycline: A glycylcycline that inhibits protein synthesis.
Teicoplanin: Another glycopeptide with a similar mechanism of action.
This compound’s uniqueness lies in its ability to treat severe infections caused by antibiotic-resistant bacteria, making it a vital tool in modern medicine .
Biological Activity
Vancomycin is a glycopeptide antibiotic that plays a crucial role in the treatment of serious infections caused by Gram-positive bacteria, particularly those resistant to other antibiotics. This article delves into its biological activity, mechanisms of action, and recent research findings, including case studies and data tables.
This compound primarily exerts its antibacterial effect by inhibiting cell wall synthesis in bacteria. It binds to the D-alanyl-D-alanine terminus of cell wall precursor units, preventing their incorporation into the growing cell wall. This action leads to cell lysis and death, particularly in rapidly dividing bacteria. Additionally, this compound has been shown to alter the permeability of bacterial cell membranes and inhibit RNA synthesis, further contributing to its antimicrobial effects .
Antibacterial Spectrum
This compound is effective against a broad range of Gram-positive organisms, including:
- Staphylococcus aureus (including MRSA)
- Streptococcus pneumoniae
- Enterococcus faecium (including this compound-resistant strains)
- Clostridium difficile
Despite its effectiveness, this compound has limited activity against Gram-negative bacteria due to its large molecular size and inability to penetrate the outer membrane .
Recent Research Findings
Recent studies have focused on enhancing the efficacy of this compound through various modifications and combinations:
- Novel Derivatives : Research indicates that introducing quaternary ammonium cations into this compound can significantly improve its antibacterial activity. For instance, a derivative known as QAV-a1 showed higher survival rates in infected mice compared to standard this compound at higher doses .
- Conjugation with Cell-Penetrating Peptides (CPPs) : Studies demonstrated that conjugating this compound with CPPs like Tat (47–57) enhances its antimicrobial properties. The cytotoxicity of these conjugates was evaluated, showing varied effects on cell viability at different concentrations .
- Biofilm Activity : this compound's efficacy against biofilms is notably lower than its activity against planktonic cells. Modifications such as dipicolylamine functionalization have been explored to enhance its effectiveness against biofilm-associated infections .
Case Studies
Several case studies illustrate the clinical application of this compound:
- Case Study 1 : A patient with MRSA bacteremia was treated with this compound combined with an aminoglycoside, resulting in a successful outcome. The combination therapy demonstrated enhanced efficacy compared to monotherapy, highlighting the importance of synergistic effects in treatment .
- Case Study 2 : In a pediatric population, the emergence of resistance to this compound was monitored. Despite concerns about resistance patterns, no significant increase was observed over three decades, indicating sustained effectiveness against common pathogens .
Table 1: Efficacy of this compound Against Various Bacterial Strains
| Bacterial Strain | Minimum Inhibitory Concentration (MIC) | Resistance Status |
|---|---|---|
| Staphylococcus aureus (MRSA) | 1 µg/mL | Sensitive |
| Enterococcus faecium | 8 µg/mL | VanA phenotype |
| Streptococcus pneumoniae | 0.5 µg/mL | Sensitive |
| Clostridium difficile | 4 µg/mL | Sensitive |
Table 2: Comparative Survival Rates in In Vivo Studies
| Treatment | Dosage (mg/kg) | Survival Rate (%) |
|---|---|---|
| This compound | 40 | 33.3 |
| QAV-a1 | 40 | 100 |
Properties
CAS No. |
1404-90-6 |
|---|---|
Molecular Formula |
C66H75Cl2N9O24 |
Molecular Weight |
1449.2 g/mol |
IUPAC Name |
48-[3-[(4S)-4-amino-5-hydroxy-4,6-dimethyloxan-2-yl]oxy-4,5-dihydroxy-6-(hydroxymethyl)oxan-2-yl]oxy-22-(2-amino-2-oxoethyl)-5,15-dichloro-2,18,32,35,37-pentahydroxy-19-[[4-methyl-2-(methylamino)pentanoyl]amino]-20,23,26,42,44-pentaoxo-7,13-dioxa-21,24,27,41,43-pentazaoctacyclo[26.14.2.23,6.214,17.18,12.129,33.010,25.034,39]pentaconta-3,5,8(48),9,11,14,16,29(45),30,32,34(39),35,37,46,49-pentadecaene-40-carboxylic acid |
InChI |
InChI=1S/C66H75Cl2N9O24/c1-23(2)12-34(71-5)58(88)76-49-51(83)26-7-10-38(32(67)14-26)97-40-16-28-17-41(55(40)101-65-56(54(86)53(85)42(22-78)99-65)100-44-21-66(4,70)57(87)24(3)96-44)98-39-11-8-27(15-33(39)68)52(84)50-63(93)75-48(64(94)95)31-18-29(79)19-37(81)45(31)30-13-25(6-9-36(30)80)46(60(90)77-50)74-61(91)47(28)73-59(89)35(20-43(69)82)72-62(49)92/h6-11,13-19,23-24,34-35,42,44,46-54,56-57,65,71,78-81,83-87H,12,20-22,70H2,1-5H3,(H2,69,82)(H,72,92)(H,73,89)(H,74,91)(H,75,93)(H,76,88)(H,77,90)(H,94,95)/t24?,34?,35?,42?,44?,46?,47?,48?,49?,50?,51?,52?,53?,54?,56?,57?,65?,66-/m0/s1 |
InChI Key |
MYPYJXKWCTUITO-BSRCFTEOSA-N |
SMILES |
CC1C(C(CC(O1)OC2C(C(C(OC2OC3=C4C=C5C=C3OC6=C(C=C(C=C6)C(C(C(=O)NC(C(=O)NC5C(=O)NC7C8=CC(=C(C=C8)O)C9=C(C=C(C=C9O)O)C(NC(=O)C(C(C1=CC(=C(O4)C=C1)Cl)O)NC7=O)C(=O)O)CC(=O)N)NC(=O)C(CC(C)C)NC)O)Cl)CO)O)O)(C)N)O |
Isomeric SMILES |
CC1C([C@@](CC(O1)OC2C(C(C(OC2OC3=C4C=C5C=C3OC6=C(C=C(C=C6)C(C(C(=O)NC(C(=O)NC5C(=O)NC7C8=CC(=C(C=C8)O)C9=C(C=C(C=C9O)O)C(NC(=O)C(C(C1=CC(=C(O4)C=C1)Cl)O)NC7=O)C(=O)O)CC(=O)N)NC(=O)C(CC(C)C)NC)O)Cl)CO)O)O)(C)N)O |
Canonical SMILES |
CC1C(C(CC(O1)OC2C(C(C(OC2OC3=C4C=C5C=C3OC6=C(C=C(C=C6)C(C(C(=O)NC(C(=O)NC5C(=O)NC7C8=CC(=C(C=C8)O)C9=C(C=C(C=C9O)O)C(NC(=O)C(C(C1=CC(=C(O4)C=C1)Cl)O)NC7=O)C(=O)O)CC(=O)N)NC(=O)C(CC(C)C)NC)O)Cl)CO)O)O)(C)N)O |
Appearance |
White to off-white solid powder |
Key on ui application |
Vancomycin is an antibiotic used to treat a number of bacterial infections. It is a member of the glycopeptide antibiotic class and is effective mostly against Gram-positive bacteria. |
boiling_point |
N/A |
melting_point |
N/A |
Key on ui other cas no. |
1404-90-6 |
physical_description |
Tan to brown solid; [HSDB] |
Pictograms |
Health Hazard |
Purity |
>98% (or refer to the Certificate of Analysis) |
Related CAS |
1404-93-9 (hydrochloride) 64685-75-2 (sulfate) |
shelf_life |
When reconstituted with sterile water for injection, vancomycin hydrochloride injection is stable for 2 weeks at room temperature; the manufacturers state that reconstituted injections may be stored for 96 hours at 2 - 8 °C without substantial loss of potency. When reconstituted as directed in 0.9% sodium chloride injection or 5% dextrose injection, solutions prepared from ADD-Vantage vials of the drug are stable for 24 hours at room temperature. Vancomycin solutions containing 5 mg/mL in 0.9% sodium chloride injection or 5% dextrose injection are reportedly stable for at least 17 days when stored at 24 °C in glass or PVC containers and for at least 63 days when stored at 5 °C or -10 °C in glass containers. Following reconstitution with sterile water for injection as directed, vancomycin solutions that have been further diluted to a concentration of 5 mg/mL in 5 - 30% dextrose injection are stable when stored in plastic syringes for 24 hours at 4 eg C and then subsequently for 2 hours at room temperature. Solutions are stable for two weeks at room temp or longer if refrigerated. /Hydrochloride/ |
solubility |
White solid; solubility in water: greater than 100 mg/mL; moderately soluble in methanol; insoluble in higher alcohols, acetone, ether; UV max absorption (water): 282 nm (e = 40, 1%, 1 cm) /Vancomycin hydrochloride/ |
source |
Synthetic |
Synonyms |
AB-Vancomycin Diatracin Hydrochloride, Vancomycin Sulfate, Vancomycin Vanco Azupharma VANCO-cell Vanco-saar Vancocin Vancocin HCl Vancocine Vancomicina Abbott Vancomicina Chiesi Vancomicina Combino Phar Vancomicina Norman Vancomycin Vancomycin Hexal Vancomycin Hydrochloride Vancomycin Lilly Vancomycin Phosphate (1:2) Vancomycin Phosphate (1:2), Decahydrate Vancomycin Sulfate Vancomycin-ratiopharm Vancomycine Dakota |
Origin of Product |
United States |
Retrosynthesis Analysis
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Strategy Settings
| Precursor scoring | Relevance Heuristic |
|---|---|
| Min. plausibility | 0.01 |
| Model | Template_relevance |
| Template Set | Pistachio/Bkms_metabolic/Pistachio_ringbreaker/Reaxys/Reaxys_biocatalysis |
| Top-N result to add to graph | 6 |
Feasible Synthetic Routes
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