Glycopeptide Antibiotics: Definition, Use and Development
What are glycopeptide antibiotics?
Glycopeptide antibiotics are a class of antibiotics produced by Streptomyces or actinomyces with a complex structure containing a glycosylated peptide skeleton. It exerts its antibacterial effect mainly by inhibiting the synthesis of bacterial cell wall. They are widely used to treat serious infections caused by Gram-positive bacteria, such as methicillin-resistant Staphylococcus aureus (MRSA) and Clostridium difficile. Vancomycin is the most representative of these antibiotics, and its structure is composed of seven amino acid residues, and it binds multiple sugar groups.
Glycopeptide antibiotics typically have a large molecular weight and complex spatial configuration, resulting in poor oral absorption in the intestine, so they are often administered intravenously. But it is this complex structure that allows it to specifically interfere with bacterial growth, with less effect on human cells. They are less stable in aqueous solutions and are usually stored in dry powder form, but researchers have found ways to prepare aqueous solutions of certain glycopeptide antibiotics in cold storage or at room temperature to improve their stability.
Glycopeptide antibiotic mechanism of action
The main mechanism of action of glycopeptide antibiotics is to inhibit the crosslinking of peptidoglycan layer and prevent the synthesis of bacterial cell wall by binding to the D-alanine-d-alanine terminal of lipid II, the precursor of bacterial cell wall. This process causes bacterial cell wall defects and eventually causes bacterial cell rupture and death. The site of action is different from β-lactam antibiotics and does not compete with penicillins for binding sites. The chemical structure and mechanism of action of these antibiotics are unique, so there is no cross-resistance with other antibacterial drugs.
Resistance to glycopeptide antibiotics
The resistance mechanism to glycopeptide antibiotics mainly includes two ways: target modification and pump excretion. Target modification occurs when bacteria reduce the binding affinity of antibiotics to cell wall precursors by changing the D-alanine-D-alanine terminus of the cell wall precursor lipid II, replacing it with D-lactic acid or D-serine. In addition, bacteria can acquire drug-resistant genes, such as VanA type glycopeptide resistance nanomachines, through horizontal gene transfer, which involves gene clusters encoding D-D-aminopeptidase (vanX), D-D-aminopeptidase (vanY), and a ninth gene with unknown function (vanZ).
The pump excretion mechanism is to expel antibiotics outside the cell through a series of excretion pumps, thereby reducing the concentration of antibiotics in the cell, so that it can not effectively play a role. For example, Teicoplanin-associated site regulators (TcaR) in Staphylococcus aureus belong to a family of multidrug resistance regulators involved in teicoplanin and methicillin resistance in Staphylococcus aureus.
Examples and uses of glycopeptides
Vancomycin
Vancomycin was discovered in 1952 and Streptomyces orientalis is the microbe that produces vancomycin. It has strong antibacterial activity against a variety of gram-positive strains, including penicillin-resistant Staphylococcus aureus. The successful application of vancomycin subsequently led to the discovery and development of teicoplanin, the only other natural product glycopeptide antibiotic used clinically.
The antibacterial activity of vancomycin can be attributed to its ability to bind tightly to lipid II, a precursor of the bacterial cell wall, thereby inhibiting cell wall biosynthesis. More specifically, vancomycin interacts with the D-Ala-D-Ala terminus of lipid II through a well-defined network of penta-hydrogen bonds. This interaction effectively isolates lipid II and spatially blocks subsequent transglycosylation and transpeptide steps, ultimately leading to inhibition of cell wall biosynthesis.
Vancomycin has been found to be effective in treating a variety of conditions, including endocarditis, skin and skin structure infections (SSSIs), bone infections, and airway infections. Although vancomycin can be taken orally, intravenous administration is preferred due to its poor oral bioavailability. Vancomycin has a relatively low protein binding (<50%) in="" healthy="" adults="" with="" a="" half-life="" of="" 6-12="" hours="" and="" elimination="" the="" unmetabolized="" portion="">80%) primarily by renal excreta. Long-term slow infusion of vancomycin is clinically recommended.
Structure of two natural glycopeptide antibiotics vancomycin and teicoplanin used in clinic. (Van Groesen, E., 2022)
Lipoglycopeptide antibiotic: Teicoplanin
The lipoglycopeptide antibiotic teicoplanin is isolated from the actinomyces Teicoplanin. The most notable difference between teicoplanin and vancomycin is the presence of a hydrophobic acyl tail attached to the central monosaccharide portion (amino acid 4), which is the non-acylated disaccharide group in vancomycin. Travancin is active against a variety of gram-positive bacteria. It prevents the polymerization of n-acetylmuramic acid (NAM) and n-acetylglucosamine (NAG) and crosslinking of peptidoglycan by binding with D-Ala-D-Ala. Bacterial cell wall synthesis is thus inhibited. In addition, due to the lipophilic side chain portion, Travansin disrupts membrane potential and cell permeability. This additional bactericidal mechanism distinguishes Travancin from vancomycin.
In Europe, teicoplanin is approved for SSSIs, endocarditis, complex urinary tract infections, bone and joint infections, pneumonia and bacteremia caused by gram-positive infections, usually by intravenous and intramuscular injection. Due to its lower overall incidence of adverse effects (including reduced nephrotoxicity), teicoplanin is more favorable for clinical use when considering its toxic profile compared to vancomycin. The discovery of teicoplanin, a natural lipoglycopeptide, sparked interest in the development of semi-synthetic lipoglycopeptide antibiotics. To date, three antibiotics have been approved for clinical use: Telavancin, dalbavancin, and oritavancin.
Glycopeptide antibiotics at BOC Sciences
Advances in semi-synthetic glycopeptide antibiotics
In order to solve the resistance of vancomycin and other glycopeptide antibiotics, a lot of work has been done to design semi-synthetic analogues of natural glycopeptides. Compared with total synthesis, semi-synthetic methods are more time - and cost-efficient, and three novel glycopeptide antibiotics have entered the clinic.
Glycopeptides modification sites and chemistry the structural modifications performed during the production of new semi-synthetic glycopeptides occur primarily at four identified locations: the vancosamine primary amino group (Vv), C-terminal (Vc), N-terminal (Vn), and resorcinol portion (Vr). These four modification sites have been used to introduce a wide variety of structural modifications with the following five main purposes: (1) Improve binding to the bacterial cell surface; (2) Realize multiple modes of action by adding additional binding parts; (3) Drive glycopeptide dimerization to enhance localization to the target site; (4) Delivering the drug to a specific target site in the body; (5) To expand the antibacterial activity spectrum of Gram-negative strains.
A research team from Leiden University in the Netherlands has developed a class of highly effective semi-synthetic glycopeptide antibiotics-guanidino lipoglycopeptides, which contain a positively charged guanidyl group and bind a variable lipid group, by selectively modifying vancomycin in vancomycin by reducing amination and introducing lipidyl guanidine at the Vv site. These glycoleptides have shown enhanced in vitro activity against a range of Gram-positive bacteria, including clinically relevant methicillin-resistant MRSA and vancomycin-resistant strains, with little toxicity to eukaryotic cells and a low propensity for resistance selection. The binding affinity of guanidino lipoglycopeptides to the bacterial cell wall precursor lipid II was higher than that of vancomycin. Binding experiments showed that these guanidino lipoglycopeptides not only bind to wild-type D-Ala-D-Ala lipid II, but also to vancomycin-resistant D-Ala-D-Lac variants, providing insights into the enhanced activity of guanidino lipoglycopeptides against vancomycin-resistant strains.
References
- Van Groesen, E., et al. Recent advances in the development of semisynthetic glycopeptide antibiotics: 2014–2022. ACS Infectious Diseases. 2022, 8(8): 1381-1407.
- Van Groesen, E.,et al. Semisynthetic guanidino lipoglycopeptides with potent in vitro and in vivo antibacterial activity. Science Translational Medicine. 2024, 16(759): eabo4736..
