Glycopeptides (Vancomycin and Teicoplanin): Mode of Action and Resistance

A patient with a serious methicillin-resistant Staphylococcus aureus (MRSA) bloodstream infection is started on vancomycin, the drug held in reserve for exactly this situation. For decades vancomycin has been the reliable last line against resistant gram-positive infections.

Sometimes antimicrobial susceptibility report carries a warning that would have been unthinkable a generation ago: reduced vancomycin susceptibility. Understanding how vancomycin works, why it succeeds where penicillins fail, and how bacteria are learning to resist it, is essential to using this last-line drug well.

What are glycopeptides?

Glycopeptides are a class of antibiotics that kill bacteria by blocking cell wall synthesis, but through a completely different route from the beta-lactams.

Vancomycin is the most important and most widely used member; teicoplanin is the other classic glycopeptide. They are active against most gram-positive organisms, including MRSA, but not against gram-negative bacteria.

Most gram-negative bacteria are intrinsically resistant to vancomycin because their outer membrane is impermeable to the large glycopeptide molecule, a good example of the intrinsic resistance discussed in Antibiotic Resistance.

Do you know? Vancomycin was isolated in 1953 by E.C. Kornfeld and colleagues at Eli Lilly, from a soil sample collected in the jungles of Borneo. It is a fermentation product of the actinomycete then called Streptomyces orientalis (later renamed Amycolatopsis orientalis). The crude brown compound was nicknamed "Mississippi mud," and the drug was named vancomycin, from the word "vanquish."

Why glycopeptides matter

Glycopeptides are a reserve class: they are what clinicians turn to when first-line drugs fail. Vancomycin remains first-line for serious MRSA infections and, given orally, is a mainstay for Clostridioides difficile colitis. Because glycopeptides are not beta-lactams, they are also an option for gram-positive infections in patients with penicillin allergy.

That reserve status is exactly why the emergence of resistance, in enterococci (VRE) and, more alarmingly, in S. aureus (VISA and VRSA), matters so much: when the last-line drug fails, there are few options left.

Structure

Glycopeptides are built around an aglycone core, a highly conserved seven-amino-acid (heptapeptide) chain bearing two chloride groups, with two or more sugars attached. The aglycone core is the part that does the antibacterial work, while the sugars adjust the molecule's solubility and its tendency to form dimers.

Figure: Structure of vancomycin and teicoplanin

The lipoglycopeptides (dalbavancin, oritavancin, and telavancin) are newer semisynthetic derivatives that add a fatty (hydrophobic) tail, which gives them extra properties such as a longer half-life and, for some, activity against resistant strains.

Classification and members

Mode of action of vancomycin

Here is the key contrast every student should hold onto: beta-lactams inhibit the enzyme (the penicillin-binding protein, PBP), while vancomycin blocks the substrate. Vancomycin does not bind PBPs at all. Instead it binds directly to the D-alanyl-D-alanine (D-Ala-D-Ala) terminus of the peptidoglycan precursor as the cell wall is being built. By capping that terminus, vancomycin physically prevents the transpeptidase and transglycosylase enzymes from reaching it, so the new peptidoglycan cannot be cross-linked or elongated. Cell wall synthesis stops, and the bacterium dies.

Figure: Biosynthesis of Staphylococcal peptidoglycan

Because vancomycin attacks a step in cell wall synthesis, it belongs to the same broad family as the beta-lactams among the five mechanisms of action of antibiotics, even though it acts at a different point. The molecule is too large to cross the gram-negative outer membrane, which is why its activity is limited to gram-positive bacteria.

Figure: Mechanism of action of vancomycin and resistance

Clinical uses

Vancomycin is used intravenously for serious infections caused by MRSA and other resistant gram-positive organisms, including bacteremia, endocarditis, skin and soft-tissue infections, and pneumonia, and as empiric therapy when a resistant gram-positive infection is suspected.

Given orally (where it stays in the gut and is not absorbed), vancomycin treats Clostridioides difficile colitis. It is also a valuable option for gram-positive infections in penicillin-allergic patients. Teicoplanin has a similar spectrum with a longer half-life that allows once-daily dosing.

Side effects and monitoring

The best-known reaction is "red man syndrome," a flushing of the upper body caused by rapid infusion triggering histamine release. It is an infusion-rate reaction, not a true allergy, and slowing the infusion usually prevents it.

Vancomycin can also cause nephrotoxicity and, less often, ototoxicity, so serum levels (or AUC-based dosing) are monitored to keep the dose effective but safe.

Resistance to glycopeptides

The general principle is target alteration, one of the mechanisms of antibiotic resistance: the bacterium changes the very target vancomycin binds. Because vancomycin grips the D-Ala-D-Ala terminus, resistant bacteria simply change that terminus so the drug can no longer hold on.

Vancomycin-resistant enterococci (VRE) were reported in Europe in 1986 and in the United States in 1987. Resistance is grouped into phenotypes designated VanA through VanG. They work by remodeling the peptidoglycan terminus in one of two ways:

• D-Ala-D-Lactate (VanA, VanB, VanD): the terminal changes from D-Ala-D-Ala to D-Ala-D-Lac, which vancomycin binds about 1,000 times more weakly.
• D-Ala-D-Serine (VanC, VanE, VanG): a smaller change that also lowers binding.

In S. aureus, reduced vancomycin susceptibility takes two distinct forms that students often confuse:

• VISA (vancomycin-intermediate S. aureus) resists by building a thickened cell wall with many extra D-Ala-D-Ala targets that trap vancomycin in the outer layers before it reaches the membrane. It is not caused by the van genes.
• VRSA (vancomycin-resistant S. aureus) resists by acquiring the vanA gene itself. All VRSA isolates to date have carried vanA, most in patients co-infected with vanA-carrying VRE and MRSA, so it is thought that VRE transferred vanA to MRSA (via a plasmid or transposon) to create VRSA.

Detecting VISA and VRSA reliably needs an MIC-based method rather than a simple disk test, because disk diffusion does not separate susceptible from intermediate strains.

The full laboratory detection workflow (broth microdilution, agar dilution, the vancomycin screen agar plate, and the automated systems) is covered in the susceptibility-testing article.

How to remember

Vancomycin blocks the substrate, beta-lactams block the enzyme. Both stop cell wall cross-linking, but vancomycin caps the D-Ala-D-Ala brick while beta-lactams jam the PBP mason. This one contrast answers most exam questions about the two classes.

Resistance in one line: change the last two letters. Vancomycin grabs D-Ala-D-Ala, so resistant bacteria swap the terminal to D-Ala-D-Lac (VanA, the strong one) or D-Ala-D-Ser (VanC), and the grip is lost.

VISA versus VRSA: VISA thickens the wall (a physical trap, intermediate MIC), VRSA changes the target with vanA (true resistance, high MIC).

Where students actually get confused

Vancomycin is not a beta-lactam. It contains no penicillin ring and does not bind PBPs, so it is safe to use in penicillin allergy, and the same is true of teicoplanin.

VISA and VRSA are different mechanisms, not just different severities. VISA traps vancomycin in a thickened wall; VRSA alters the target with the vanA gene borrowed from VRE. The MIC numbers follow from the mechanism.

Red man syndrome is not an allergy. It is a histamine reaction to fast infusion, and slowing the drip usually prevents it, so it does not mean the patient can never receive vancomycin.

Why vancomycin fails against gram-negatives. It is not "resistance" that developed; the molecule is simply too big to cross the gram-negative outer membrane, so these bacteria are intrinsically resistant.

Key exam facts

References

1. Levine DP (2006). Vancomycin: a history. Clinical Infectious Diseases. 42(Suppl 1): S5-S12.
2. Courvalin P (2006). Vancomycin resistance in gram-positive cocci. Clinical Infectious Diseases. 42(Suppl 1): S25-S34.
3. Schafer M, Schneider TR, Sheldrick GM (1996). Crystal structure of vancomycin. Structure. 4(12): 1509-1515.
4. Centers for Disease Control and Prevention. Laboratory detection of vancomycin-intermediate and vancomycin-resistant Staphylococcus aureus (VISA/VRSA). CDC.
5. Blaskovich MAT, Hansford KA, Butler MS, Jia Z, Mark AE, Cooper MA (2018). Developments in glycopeptide antibiotics. ACS Infectious Diseases. 4(5): 715-735.