Close search

Vancomycin Mechanism of Action | Learn About Cell Wall Synthesis in Susceptible Bacteria & More

Vancomycin Mechanism of Action | Learn About Cell Wall Synthesis in Susceptible Bacteria & More
31 Oct 2020 Blog

History of Vancomycin

Vancomycin (brand name: Vancocin®) is a glycopeptide antibiotic with a history that can be traced back to the 1950s when it was discovered in soil produced by the organism Streptomyces orientalis. [1]

Vancomycin protected the nutrient supply needed by Streptomyces orientalis by creating and dispersing the antimicrobial, resulting in the inhibition of many of the other bacteria species that may enter its territory. After discovering that vancomycin had this activity, infectious disease researchers began to explore what uses the substance could have in healthcare as a drug for severe bacterial infections in humans.

Originally, vancomycin was considered to be a drug of last resort [2] as penicillins were effective for most infections and the risk of adverse effects were higher for vancomycin than other antibacterial drugs.

Over time, however, the development of drug resistance, improvement in purification, and the advancement of drug monitoring techniques brought vancomycin to be much more common in healthcare. Today, vancomycin is frequently used for diseases such as endocarditis, pneumonia, meningitis, osteomyelitis, enterocolitis, and skin and soft tissue infections.

It was through laboratory testing that the mechanism of action of vancomycin was discovered.

Microbiology

Cell Wall Bacteria Microbiology and Vancomycin Mechanisms of Action

Antibiotics destroy or inhibit bacteria growth by interfering with the normal processes of the bacterial cell. Many antibiotics in use today are active against the cell wall of a dividing bacterium.

The bacterial cell wall is an extremely important barrier that bacteria use to stay alive. This cell wall is made mostly of peptidoglycan, which is a mesh-like structure made of proteins (peptides) and sugars (glycan). In order for a bacterium to replicate, it must build a new peptidoglycan cell wall.[3]

Cell walls are not present in human or animal cells. Fortunately, the bacterial cell wall is an essential component of the cell, and without it the bacteria are destroyed.

By targeting components of bacteria that are not present in humans, clinicians can selectively eradicate bacterial infections while avoiding significant collateral damage to the patient.

Each bacterium is unique in their response and susceptibility to medication therapies. Proper identification of the infecting organism is of vital importance to ensure that antibiotics will be effective.

Most bacteria can be divided into two groups: gram positive and gram negative. These categories were discovered by the physician Hans Christian Gram in 1884.[4] Dr. Gram applied dyes (known as stains) to different bacteria.

In his experiment, a purple dye is applied, followed by a binding agent and a solvent such as ethanol or acetone that tries to wash away the dye. This is then followed by a pink counterstain. Dr. Gram noticed that certain bacteria could retain the purple dye, while others would allow the dye to be washed away and would appear pink.

Bacterial Cell Wall

The underlying mechanism for these differences rests primarily in the bacterial cell walls of both types of bacteria. Bacteria with a thick wall would retain the dye, appear purple, and be known as “gram positive,” while bacteria with a thin wall would allow the purple dye to wash away and stain pink with the counterstain.

These bacteria were known as “gram negative.” Dr. Gram’s technique is now known as “Gram staining.” This procedure is still in use today to guide initial antibiotic therapies in patients before the infecting bacteria can be identified.

Gram positive bacteria with their thicker cell wall also have other defining characteristics that separate them from gram negative bacteria. Most importantly for antibiotics, the cell wall for gram positive bacteria is exposed to the environment outside the cell. For gram negative bacteria, the much thinner cell wall is shielded by a membrane of fats and proteins known as a lipid bilayer.[3]

The lipid bilayer on the outside of gram-negative bacteria allows it to be much more selective regarding what can and cannot enter the cell. These bilayers must still allow some transport across its surface, however, to allow the bacteria to absorb the essential nutrients from the environment it needs to replicate.[3]

Bacteria facilitate this nutrient transport into their cells using small channels known as porins.[5] Antibiotics targeted against gram negative bacteria must have a small enough size to be able to cross through these porin channels or diffuse passively across the lipid bilayer. This lipid bilayer also has polar and non-polar components, making passive diffusion of charged molecules difficult.[6]

Vancomycin Pharmacology & Pharmacokinetics

Vancomycin Dosing - Pharmacology and Pharmacokinetics

Vancomycin is an antibacterial medication in the glycopeptide class.[7] Like penicillin, vancomycin prevents cell wall synthesis in susceptible bacteria. The main difference in the mechanism of action between the two antimicrobials is in the binding site of each.

Beta-lactam antimicrobials such as penicillin bind to the aptly named “penicillin binding proteins” as their mode of action.[8] Vancomycin binds to the acyl-D-ala-D-ala portion of the growing peptidoglycan cell wall, which is a group of amino acids. By binding, multiple mechanisms of action begin to take place resulting in bacterial inhibition.[9]

First, vancomycin uses its large size to block the cross-linking of the peptidoglycan wall. The incorporation of cross-links to the peptidoglycan mesh help to keep the cell wall strong, and without them, the wall doesn’t form correctly.

The bacterium detects that the cell wall is not functioning normally and attempts to repair it by making more peptidoglycan substrates.

The cell produces excess peptidoglycan substrates as a result, which then activates a feedback loop where degradative enzymes that break down peptidoglycan are activated. These enzymes then may also contribute to cell wall destruction and a reduction in cell wall biosynthesis.[10]

When attempting to divide, the lack of a cell wall causes the bacterium to flood with fluid from its environment, forcing it to swell and eventually burst, destroying the cell.[11] Because of this activity, both the beta-lactam antibiotics such as penicillin and the glycopeptide antibiotics such as vancomycin are considered “bactericidal.”

Vancomycin Antimicrobial Effectiveness

Reaching the exposed cell wall in gram positive bacteria is fairly easy for both penicillin and vancomycin. Penicillin and vancomycin differ substantially in size and charge, however.

While penicillin can get through the lipid bilayer “shield” of gram-negative bacteria, vancomycin is nearly three times larger and it has a net positive charge. Because of this, vancomycin cannot enter the gram-negative bacterial cell and therefore the drug has no activity against nearly all gram-negative infections.[6]

Unfortunately for vancomycin, the size of the drug also limits the antimicrobial’s effectiveness when administered orally to strictly treating colitis. When given by mouth, vancomycin cannot cross from the gastrointestinal tract into the blood in amounts necessary to treat a systemic infection.[11]

This also means that oral vancomycin is much less likely to cause the same side effects such as kidney damage (nephrotoxicity), red man syndrome, or hearing loss (ototoxicity) that is possible with the intravenous version. It also means that the oral version typically does not require pharmacokinetic monitoring of drug levels, excretion rates, or its half-life. Orally administered vancomycin is used for its antimicrobial activity in intestinal infections such as colitis caused by Clostridoides difficile (previously known as Clostridium difficile or C. difficile).[7]

Vancomycin Resistance

Stpahylococcus aureus and Vancomycin Resistance

With antibiotic use comes the development of resistant strains of bacteria. Vancomycin is typically used for suspected or known Staphylococcus aureus (Staph) or infections. It is also active against a variety of other common gram-positive bacteria, such as the streptococci and enterococci species. Specifically, vancomycin is used for resistant bacteria where other options such as beta-lactams are not effective.

One such type of resistant bacteria where vancomycin is used are those that are resistant to methicillin, a type of penicillin. A well-known resistant bacteria harboring this trait is Staphylococcus aureus. This type of resistant bacteria is known as methicillin-resistant Staphylococcus aureus or MRSA.

MRSA developed this resistance through years of different penicillins being used to treat or control the bacterium. As our knowledge of bacteria and their resistance patterns continued to develop, beta-lactam antibiotics were combined with beta-lactamase inhibitors that were capable of extending their spectrum of activity. Unfortunately, this still was not enough. Even when combined with beta-lactamase inhibitors, penicillins started to lose their antimicrobial activity against certain strains of S. aureus, selecting for an increasing incidence of MRSA.

Luckily, while MRSA is resistant to penicillins, development of in-vitro resistant strains to vancomycin remains rare. One type of resistance that staphylococci can develop is transferred to MRSA from another bacteria genus, the vancomycin-resistant enterococci or VRE.[12]

This form of enterococci carries a gene that changes the acyl-D-ala-D-ala amino acid chain to acyl-D-ala-D-lactate. This change still allows the peptidoglycan wall to form, but it also causes antibiotic resistance by severely limiting vancomycin binding. A strain of Staphylococcus aureus exhibiting this resistance profile may be referred to as VRSA or vancomycin-resistant Staphylococcus aureus. This usually requires changing the drug to another antibacterial agent.

Vancomycin Adverse Effects

Vancomycin Mechanism of Action - Adverse Effects and Nephrotoxicity

Vancomycin therapy can also cause kidney damage (nephrotoxicity) if not carefully monitored, and the mechanisms of action of this side effect are not well understood.[13] The difference between effective therapy and the risk of this adverse effect is narrow.

As a method to reduce the toxicity of the drug while maintaining its therapeutic effect, software programs such as DoseMeRx provide clinicians with highly accurate methods of analyzing a patient’s drug levels. This dosing strategy is known as area-under-the-curve or AUC monitoring, and it was recommended as the method of choice to monitor vancomycin therapy in the 2020 vancomycin consensus guidelines.[14]

Conclusions

Vancomycin Mechanism of Action - Thick Bacterial Cell Wall Peptidoglycan

The mechanism of action of vancomycin can be explained by remembering that bacteria need a strong cell wall to protect it. This wall is made of peptidoglycan, a mix of proteins and sugars. Gram-positive bacteria have a thick cell wall that is exposed to the fluid in the environment around the cell. Gram-negative bacteria have a thin cell wall that is surrounded by a lipid bilayer.

This lipid bilayer doesn’t allow vancomycin to enter gram-negative cells, and therefore it has no activity against this type of bacteria. When it reaches the cell wall of an actively dividing susceptible gram-positive bacterium, vancomycin binds to the acyl-D-ala-D-ala portion of the growing cell wall. After binding, it prevents the cell wall from forming the cross-linking necessary to keep it strong.

The bacterial cell reacts, making more peptidoglycan substrates. These precursors build up in the cell and cause an increase in bacterial enzymes that destroy peptidoglycan. After the cell wall is removed or severely damaged, fluid enters the cell and causes the bacteria to swell until it finally bursts.

Vancomycin requires close monitoring to ensure the therapeutic benefits of the drug while decreasing adverse effects. Companies such as DoseMeRx provide software that allows for close monitoring of the medication to aid clinicians in their management of the patient’s drug therapy. DoseMeRx also provides software for clinicians to monitor other medications seen commonly in healthcare, such as aminoglycosides.

Request a free trial

See how easy DoseMeRx is to operate and integrate into your workday.

Request a free trial below. You can also phone us on +1 (832) 358-3308 or
email hello@doseme-rx.com.

Related Articles

New Vancomycin Dosing Guidelines Released - What You Need to Know Now
New Vancomycin Dosing Guidelines Released – What You Need to Know Now
Preparing for the New Vancomycin Guidelines – What Should You Be Considering?
Preparing for the New Vancomycin Guidelines – What Should You Be Considering?
New vancomycin guidelines - what's new?
New vancomycin guidelines – what’s new?

References

1) Levine, DP. Vancomycin: A History.Clin Infect Dis. 2006;42:S5-S12.

2) Boneca I and Chiosis G. Vancomycin resistance: occurrence, mechanisms and strategies to combat it. Expert Opin Ther Targets 2003;7(3):311-328.

3) Silhavy TJ, Kahne D, and Walker S. The bacterial cell envelope. Cold Spring Harb Perspect Biol. 2010;2(5):1-16

4) Madani K. Dr. Hans Christian Jaochim Gram: inventor of the Gram stain. Primary Care Update for OB/GYNS 2003;10(5):235-237

5) Galdiero et al. Microbe-host interactions: structure and role of gram-negative bacterial porins. Curr Protein Pept Sci. 2012;13(8):843-854

6) Livermore DM. Antibiotic uptake and transport by bacteria. Scand J Infect Dis Suppl. 1990;74:15-22

7) Patel S, Preuss CV, Bernice F. Vancomycin. StatPearls [Internet]. Last update Feb 2020.

8) Nikaido H. Crossing the envelope: how cephalosporins reach their targets. Clin Microbiol Infect. 2000;6(S3):22-26

9) Nagarajan R. Antibacterial activities and modes of action of vancomycin and related glycopeptides. Antimicrob Agents Chemother. 1991;35(4):605-609

10) Scheffers DJ and Pinho M. Bacterial cell wall synthesis: new insights from localizations studies. Microbiol Mol Biol Rev. 2005;69(4):585-607

11) Kohanski MA, Dwyer DJ, and Collins JJ. How antibiotics kill bacteria: from targets to networks. Nat Rev Microbiol. 2010;8(6):423-435

12) Gardete S and Tomasz A. Mechanisms of vancomycin resistance in Staphylococcus aureus. J Clin Invest. 2014;124(7):2836-2840

13) Bamgbola O. Review of vancomycin-induced renal toxicity: an update.Ther Adv Endocrinol Metab. 2016; 7(3):136-147

14) Rybak MJ, Le J, Lodise T, et al. Therapeutic monitoring of vancomycin for serious methicillin-resistant Staphylococcus aureus infections: A revised consensus guideline and review by the American Society of Health-System Pharmacists, the Infectious Diseases Society of America, the Pediatric Infectious Diseases Society, and the Society of Infectious Diseases Pharmacists. Am J Health-Syst Pharm. 2020; 77(11):835-864.

Vanco AUC Conversion Toolkit 📝Download Now →

HIPAA Privacy Statement | Privacy policy | DoseMe & the GDPR | Copyright © 2012 - 2020 DoseMe Pty Ltd. All Rights Reserved.
DoseMe® is a registered trademark of DoseMe Pty Ltd. DoseMeRx℠ and DoseMe℞℠ are service marks of DoseMe LLC.