Question

Vancomycin is an important antibiotic. It is isolated from the bacterium Streptomyces orientalis and functions by inhibiting bacterial mucopeptide synthesis. It is a last line of defense against the resistant Staph organisms that are now common in hospitals. In 1999, Professor Dale Boger (The Scripps Research Institute) reported a synthesis of vancomycin aglycon (aglycon = lacking a sugar) involving the following steps, among others. Compound (I) was prepared from simple starting materials by a series of steps involving forming amide bonds. (a) Suggest reasonable precursors and show how the bonds could be formed (the actual reagents used have not been introduced, but they work in a similar way to those you know). (b) Give reagents for this reaction and suggest the mechanism. One of the interesting features of this synthesis is that ring \(C\) in compound (II) (and subsequent compounds in this synthesis) has extremely hindered rotation. As a result, compound (II) exists as two atropisomers (Section 3.2) that are interconverted only at \(140^{\circ} \mathrm{C}\). (c) Show these two isomers. (II) was then converted to (III). (d) Suggest reagents to accomplish this transformation. Compound (III) was then converted to (IV). (e) Suggest reagents and the ring A fragment that could be used for this reaction. Closure of an amide link between the amine on ring A (after removal of the protecting group) and the carbomethoxy group above it led to a precursor of vancomycin. (f) Show the ring closure reaction of the deprotected free amino group and its mechanism. Another interesting feature of this synthesis is that rings \(A\) and \(B\) also form atropisomers. These can be converted into a \(3: 1\) mixture of the desired and undesired atropisomers on heating at \(120^{\circ} \mathrm{C}\). (g) Draw these atropisomers and show that only one can be converted to vancomycin. The synthesis of the aglycon was completed by functional manipulation and addition of ring \(\mathrm{E}\) by chemistry similar to that detailed earlier. Yet, another set of atropisomers (this time of ring E) was formed! However, this one was more easily equilibrated than the others; model studies had shown that the activation barrier for this set of atropisomers should be lower than that of the others.

Short answer

Answer: Vancomycin is an antibiotic that inhibits the synthesis of mucopeptides in bacteria, causing them to rupture and die. It is derived from Streptomyces orientalis and serves as a last line of defense against resistant Staph organisms in hospitals due to its unique mechanism of action, making it effective against strains that are resistant to many other antibiotics. This highlights the importance of responsible antibiotic use to preserve the effectiveness of crucial antibiotics like Vancomycin.

Step-by-step solution

Vancomycin is an antibiotic that is used to treat serious bacterial infections. Its primary function is to inhibit the synthesis of mucopeptides in bacteria, which is an essential component of their cell walls. By doing so, Vancomycin weakens the cell wall structure, ultimately causing the bacteria cells to rupture and die. #Step 2: Identify the source of Vancomycin#

Vancomycin is isolated from the bacterium Streptomyces orientalis. Streptomyces is a genus of Gram-positive bacteria that produce a variety of secondary metabolites, including antibiotics. In this case, Streptomyces orientalis produces Vancomycin, which can then be purified and used to treat bacterial infections. #Step 3: Recognize the significance of Vancomycin as a last line of defense#

Vancomycin is particularly important in hospital settings, as it is a last line of defense against resistant Staphylococcus organisms that are common in hospitals. Staphylococcus bacteria can cause serious infections, and some strains have become resistant to many other antibiotics due to the overuse and misuse of antibiotics. Vancomycin's unique mechanism of action makes it effective against these resistant strains, making it a crucial tool in combating antibiotic resistance. #Step 4: Discuss the importance of responsible antibiotic use#

As Vancomycin is a last line of defense against antibiotic-resistant Staph bacteria, it is crucial to ensure that this valuable antibiotic is used responsibly. Overuse or misuse of antibiotics can lead to the development of resistance, limiting the effectiveness of antibiotics in treating infections. Prescribing antibiotics appropriately, completing the full course of treatment, and using narrow-spectrum antibiotics when possible are important strategies to prevent the spread of antibiotic-resistant bacteria. In summary, Vancomycin is an essential antibiotic isolated from Streptomyces orientalis, which functions by inhibiting bacterial mucopeptide synthesis. It is a last resort treatment option against resistant Staph organisms often found in hospitals. Understanding its role and importance highlights the need for responsible antibiotic use to ensure the continued effectiveness of this crucial antibiotic.

Key concepts

Antibiotic Resistance

Antibiotic resistance occurs when bacteria evolve mechanisms to withstand the drugs designed to kill them, rendering treatments ineffective and infections harder to control.

Vancomycin has been a critical weapon in the fight against such resistant bacteria. The antibiotic targets and inhibits the mucopeptide synthesis essential for bacterial cell wall construction. As bacteria develop resistance to other antibiotics, vancomycin has become a last-resort option, particularly against 'superbugs' like Methicillin-resistant Staphylococcus aureus (MRSA). However, the increased reliance on vancomycin has led to the emergence of vancomycin-resistant organisms, setting off alarm bells about the necessity for prudent antibiotic use and development of new antibiotics.

Mucopeptide Synthesis Inhibition

One of the vital processes in bacterial life is the synthesis of mucopeptides, which are the building blocks of bacterial cell walls. Vancomycin's therapeutic efficacy hinges on its ability to inhibit this synthesis.

The drug binds to the D-Ala-D-Ala dipeptide on the mucopeptide precursor, preventing the transpeptidation or transglycosylation reactions necessary for the cross-linking of peptidoglycan layers. This results in weakening of the cell wall and ultimately, the death of the bacteria. The precise targeting of mucopeptide synthesis is crucial because it affects only bacterial cells and not human cells, making vancomycin a potent antibacterial agent with relatively few side effects when used appropriately.

Streptomyces orientalis

Streptomyces orientalis is the actinobacteria from which vancomycin was originally isolated. This microorganism is part of the Streptomyces genus, known for their soil-dwelling habits and for being prolific producers of natural antibiotics.

The ability of Streptomyces species to produce secondary metabolites, such as vancomycin, is a biological adaptation for survival, eliminating competition from other microorganisms. Interestingly, their capacity to generate complex molecular structures has been a gold mine for the development of pharmaceuticals beyond antibiotics, including immunosuppressants and anticancer agents. The natural synthesis of vancomycin by Streptomyces orientalis is an intricate process involving numerous steps and unique enzymes, serving as a blueprint for the laboratory synthesis of this vital antibiotic.

Amide Bond Formation

Amide bonds are pivotal in the structure of vancomycin, as they form the linkages between different parts of the molecule. These bonds are created through a reaction between a carboxylic acid and an amine, releasing a molecule of water in a process known as a condensation reaction.

In the laboratory synthesis of vancomycin, forming these bonds requires precision to ensure the molecule’s functionality. The method of forming amide bonds has to prevent side reactions and protect functional groups on both the amine and carboxylic acid precursors until the desired stage of synthesis. Advanced techniques and reagents are used to achieve specificity in amide bond formation, thereby constructing the complex architecture of vancomycin.

Atropisomers

Atropisomerism is a type of stereoisomerism caused by the hindered rotation about a single bond, often due to steric bulk or spatial constraints. Vancomycin's synthesis results in atropisomers because certain chemical bonds in its structure have restricted rotation at room temperature.

This phenomenon is crucial during the synthesis because only one atropisomer of vancomycin has the biological activity to inhibit mucopeptide synthesis effectively. The interconversion of atropisomers typically requires the input of energy, such as heating, to overcome the energy barrier for rotation. Consequently, a mixture of desired and undesired atropisomers can be separated or equilibrated under controlled conditions. This aspect of vancomycin synthesis highlights the complexities of stereochemistry in drug development and the necessity to control chiral outcomes for effective medication.