Lipoglycopeptide: Definition, Mechanism and Advantages
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What is the lipoglycopeptide?
An antibiotic family known as lipoglycopeptides is based on glycopeptides that have lipid side chains added to them to make them more effective against bacteria and have better pharmacokinetics. This change enhances the lipoglycopeptides' interaction with bacterial cell membranes, making them more efficient in targeting bacterial cell walls and damaging their integrity. Novel lipoglycopeptides (telavancin, oritavancin, dalbavancin) are distinguished from vancomycin by the incorporation of a lipophilic side chain, which significantly alters their pharmacokinetic and/or pharmacological characteristics. In order to prevent the cross-linking process-which is crucial for the strength of bacterial cell walls-these lipoglycopeptides attach to the D-alanyl-D-alanine terminus of peptidoglycan precursors. Another effect is that they penetrate bacterial cell membranes, leading to increased permeability, membrane potential disturbance, and cell death.
Lipoglycopeptide advantages
- Enhanced potency against resistant pathogens: Lipoglycopeptides are able to disrupt cell wall production and interact directly with bacterial cell membranes due to the lipid side chains. MRSA and VRE are examples of resistant Gram-positive organisms that find it more difficult to gain resistance due to this dual mechanism.
- Extended half-life: Patients infected with Gram-positive bacteria that are resistant to many drugs have hope for therapy with the semisynthetic lipoglycopeptides dalbavancin, oritavancin, and telavancin. These drugs are able to suppress transglycosylation and transpeptidation (cell wall production) because they all include glycopeptide cores, which are heptapeptides. The three semisynthetic lipoglycopeptides exhibit distinct in vitro activity due to modifications made to the heptapeptide core. The lipophilic side chains included in all three lipoglycopeptides boost their action against Gram-positive bacteria, improve their half-life, and aid in agent anchoring to the cell membrane.
- Broad activity spectrum: Because they are effective against a broad variety of Gram-positive bacteria, lipoglycopeptides are useful in the treatment of a variety of serious infections, including as cSSTIs, HAP, and device-associated infections.
- Ability to penetrate biofilms: Bacteria frequently develop biofilms on medical equipment (e.g., catheters, heart valves) that are resistant to conventional antibiotics; lipoglycopeptides are able to break through these biofilms. Because of this quality, they are useful in the treatment of infections caused by devices.
Lipoglycopeptide antibiotics list
Oritavancin
One semi-synthetic form of chloroeremomycin is Oritavancin, a naturally occurring lipoglycopeptide. In contrast to vancomycin, chloroeremomycin has an extra aminated sugar (4-epi-vancosamine) connected to amino acid 6 of the cyclic heptapeptide and a disaccharide attached to the aglycone moiety that substitutes 4-vancosamine for 4-epi-vancosamine. The amphipathic nature of the molecule in oritavancin is due to the inclusion of a chlorobiphenylmethyl side chain to this disaccharide. This structural change enhances action against vancomycin-susceptible enterococci (VSE) as well as vancomycin-resistant enterococci (VRE), including VanA enterococci. The oritavancin dimer is stabilized and the molecule is attached to the cell membrane by means of hydrophobic interactions with its lipophilic side chain. The interactions between the disaccharides on ring 4, the 4-epi-vancosamine on ring 6, and the chlorine on ring 2 result in the creation of dimers. The formation of dimers enhances oritavancin's binding affinity for its target, which includes the VanA enterococcal D-alanyl-D-lactate (D-Ala-D-Lac). Oritavancin's superior pharmacokinetic profile, high activity in both vitro and vivo, and selection as a clinical development candidate in 1994 were its deciding factors.
Dalbavancin
Dalbavancin, an antibiotic similar to teicoplanin A-40926, is a semisynthetic lipoglycopep tide. There is a three-step process to synthesize dalbavancin from A-40926, an agent that is naturally generated by the actinomycete Non-omuria spp. In order to make dalbavancin more effective against staphylococci, particularly coagulase-negative staphylococci (CoNS), it is necessary to amidate the peptide carboxyl group in the teicoplanin structure with a 3,3 dimethylamino-propylamide group. Dalbavancin is distinct from teicoplanin because it has a terminal me thylamino group, a chlorine atom, and an absence of the acetylglucosamine group. In an attempt to enhance dalbavancin's effectiveness against VanAenterococci, the acetyl glucosamine group was intentionally removed. However, this pathogen continued to be resistant to dalbavancin even after this change. Ring 4 of dalbavancin is different from acylglucosamine in that it contains an acylaminoglu curonate. The long lipophilic side chain in dalbavancin has two functions: first, it increases the antibacterial action by increasing its affinity for the terminal D-Ala-D-Ala; second, it anchors the drug to the membrane, which allows for once-weekly dosage; and third, it extends the half-life.
Telavancin
Adding a hydrophobic and a hydrophilic group to the vancomycin structure sets telavancin, a semisynthetic derivative of vancomycin, apart from the parent molecule. At the 40 position of ring 7 the hydrophilic (phosphomethyl) aminomethyl moiety is found. The reason telavancin is classified as a lipoglycopeptide is the hydrophobic decylaminoethyl moiety linked to the vancosamine sugar. The decylaminoethyl lipophilic chain gives telavancin the capacity to connect to cell membranes, a function which confirms the antibacterial binding affinity for the D-Ala-D-Ala target site. Tela vancin's action against both MRSA phenotypic and non-VanAenterococci also results from the lipophilic side chain. The length of the lipophilic side chain is crucial as longer chains boost agent activity against enterococci but lower activity against MRSA. Clearly, the 10-carbon lipophilic side chain discovered in telavancin is a compromise between optimum enterococci and MRSA activity as a 13-carbon chain is desirable for maximum activity against enterococci. Whereas the presence of a chlorine atom on ring 2 boosts the binding affinity of telavancin for its target binding site, the lipo saccharide moiety in telavancin reduces peptido glycan generation by inhibition of transglycosylases. The negatively charged hydrophilic group present not only helps to remove the medicine but also lowers any possible nephrotoxic effects and increases the capacity of telavancin to diffuse into tissues.
Chemical structure of lipoglycopeptides (telavancin, oritavancin, dalbavancin) as compared to conventional glycopeptides. (Zhanel G G., et al., 2010)
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Lipoglycopeptide mechanism of action
Because all lipoglycopeptides keep the aglycone moiety of conventional molecules in their structure, they also con serve this primary mode of action. Yet their specific chemical features confer to them additional antibacterial properties. An early work suggested that the interaction between glycopeptides and the D-Ala-D-Ala motif can be enhanced by two mechanisms, namely (a) the formation of homodimers between glycopeptide molecules, which confers a structural rigidity that locks the binding pocket into the correct conformation and may allow for a coop erative binding to the ligand, and (b) the anchoring of the antibacterial in the membrane, which may help to maintain the drug close to its target.
It has been demonstrated that oritavancin forms dimers through the extra 4-epi-vancosamine sugar, which flips the molecule around so that it may bind to the ligand cooperatively. Even without a ligand, dalbavancin may form a robust dimer through its lipophilic side chains in solution. In this instance, though, the molecule adopts a "closed" conformation upon ligand engagement and neither dimer formation nor contact with cell wall precursors work together to enhance the antibacterial activity. Oritavancin and telavancin are known to attach to membranes through a lipophilic side chain that is connected to the disaccharide group. Because of their effects on cell wall synthesis and/or activation of autolysins, these compounds also lead to abnormal septum development and the lack of staining of nascent septal cross walls in electron microscopy. However, oritavancin possesses the unusual ability to persist against staphylococci and vancomycin-resistant enterococci (VRE).
Telavancin has a unique, high-affinity interaction with lipid II, resulting in membrane depolarization, bacterial lysis, and a fast bactericidal effect. Microarray analyses demonstrated that following 15 minutes of drug exposure, there was a pronounced expression of the cell wall stress stimulon, indicative of the inhibition of cell wall biosynthesis. This was subsequently accompanied after 60 minutes by the induction of various genes, which were also influenced by other membrane-depolarizing agents. These observations corroborate a twofold mode of action and may elucidate the bimodal configuration of concentration–effect correlations in kill curve tests.
In addition to causing membrane depolarization in bacterial cells and liposomes reconstituted from S. aureus lipids, oritavancin compromises membrane integrity. The enhanced efficacy of oritavancin against vancomycin-resistant organisms may be attributable to its ability to bind selectively to lipidII; this is in contrast to its progenitor, chloreremomycin, which has fewer interaction sites. Oritavancin has two binding sites on the lipid-linked disaccharide-pentapeptide monomers in S. aureus, according to solid-state nuclear magnetic resonance (NMR) studies. These sites are on the D-Ala-D-Ala termini, similar to vancomycin, and on the pentaglycyl bridging segment, which it binds to via its lipophilic side chain on the dissacharide and other components of its aglycon structure. Because of this, it is able to hinder the extensions of precursor chains caused by transglycosylase and the cross-linking of precursors caused by transpeptidase. Because oritavancin preferentially interacts with several places on the peptidic bridge, its inhibition of transpeptidase becomes much more evident in Enterococcus faecium. The drug's focus has shifted away from transglycosylase activity because of the diminished importance of interactions with D-Ala-D-ala termini. Even more crucially, this explains why vancomycin-resistant bacteria can still be inhibited by oritavancin.
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Spectrum of activity of lipoglycopeptide antibiotic
As with glycopeptides, lipoglycopeptides have a large molecular weight that prevents them from penetrating bacterial cell walls and membranes. As a result, they are only effective against Gram-positive bacteria, where their target is readily available. Although many studies have looked at these compounds' in vitro activity against collections of Gram-positive clinical isolates, many of those studies didn't use polysorbate-80, which is necessary to prevent the drugs from adsorbing to the plastic, because they were using broth without it. Accordingly, the emphasis in Table 1 is on more recent investigations that have followed the method presently advocated by the Clinical Laboratory Standards Institute (CLSI), namely, the addition of 0.002% polysorbate-80 to the culture media. These three medications are more effective than vancomycin and have MIC distributions that are quite comparable to one another when used against staphylococci, streptococci, and enterococci that are susceptible to vancomycin. However, there is a direct relationship between the vancomycin MIC and the lipoglycopeptide MICs; therefore, the MIC of vancomycin may be used to predict the likelihood of being susceptible to lipoglycopeptides. In terms of effectiveness against enterococci, oritavancin is somewhat stronger than its competitors. In addition, no other virus retains any action against VRSA or VREs carrying the vanA genotype. Since they do not develop this particular resistance genotype, telavancin, dalbavancin, and tecoplanin continue to be effective against vanB-type resistant bacteria. Compared to MRSA, the MICs for VISA are two to four dilutions higher for all three medications.
Lipoglycopeptides, similar to vancomycin, have anti-Clostridia activity, including against C. difficile. Oritavancin has MICs between 0.125 and 2 mg/L, telavancin between 0.25 and 0.5 mg/L, and dalbavancin between 0.125 and 0.5 mg/L, with oritavancin's MICs being 1 dilution lower with polysorbate-80. Beyond its efficacy against C. diff infection after 4 days of therapy in an in vitro model of the human gut, oritavancin does not produce spore germination or toxin generation in either the laboratory or the living organism. Clinicians have not yet reported resistance to lipoglycopeptides; medications with many action modes are less likely to have this problem. The elimination of all precursors ending in D-Ala-D-Ala during cell wall synthesis or the expression of the accessory gene vanZ, which confers resistance to teicoplanin by an unknown mechanism, have been proposed as possible explanations for the moderate level of oritavancin resistance in enterococci in laboratory mutants. Enterococcus faecalis mutants affecting the VanSB sensor can cause mild resistance to oritavancin and teicoplanin, two drugs that do not affect the wild-type VanSB sensor. Several changes in gene expression were found in transcriptomic studies of a telavancin-resistant mutant of Staphylococcus aureus. These changes included upregulation of genes involved in stress response and cell wall or fatty acid biosynthesis, and downregulation of genes involved in lysine biosynthesis, surface protein synthesis, modulin or proteases, anaerobic metabolism, and global regulators like agr. Along with these alterations, the cell wall thickens and autolysin activity decreases, mimicking the effects seen in VISA strains.
MIC distributions of new lipoglycopeptides versus vancomycin. (Van Bambeke F. 2015)
Glycopeptides and lipoglycopeptides
Glycopeptides (such as Teicoplanin and Vancomycin) are antibiotics that obstruct bacterial cell wall production by attaching to the D-alanyl-D-alanine terminus of peptidoglycan precursors. This inhibits cross-linking, crucial for cell wall integrity, resulting in bacterial cell death. Glycopeptides have optimal efficacy against Gram-positive bacteria, as the outer membrane of Gram-negative bacteria obstructs the ingress of glycopeptides. Lipoglycopeptides are altered glycopeptides including lipid (fatty acid) side chains, enhancing their interaction with bacterial cell membranes and augmenting their efficacy. This modification improves their pharmacokinetic characteristics, frequently prolonging their half-life, so facilitating single or weekly dosage. Lipoglycopeptides function by a twofold mechanism: they impede cell wall production and compromise the bacterial cell membrane. Glycopeptides and lipoglycopeptides are essential treatments for resistant Gram-positive infections, with lipoglycopeptides providing improved flexibility, efficacy, and convenience owing to their structural alterations.
References
- Van Bambeke F. Lipoglycopeptide antibacterial agents in gram-positive infections: a comparative review, Drugs, 2015, 75(18): 2073-2095.
- Zhanel G G., et al., New lipoglycopeptides: a comparative review of dalbavancin, oritavancin and telavancin, Drugs, 2010, 70: 859-886.
- Kahne D., et al., Glycopeptide and lipoglycopeptide antibiotics, Chemical reviews, 2005, 105(2): 425-448.
- Saravolatz L D., et al., Telavancin: a novel lipoglycopeptide, Clinical infectious diseases, 2009, 49(12): 1908-1914.
- Nannini E C., et al., A new lipoglycopeptide: telavancin, Expert opinion on pharmacotherapy, 2008, 9(12): 2197-2207.
