Skip to Main Content
Skip Nav Destination

Microbial adhesion to surfaces is a suitable model to study mechanisms of cell adhesion. In addition, it is a topic of medicinal relevance, as adhesion is often a prelude to infection. Microbial colonization is extensively connected to the glycome of the host organisms and thus to the glyocalyx nature of respective host cells. This relationship might be interpreted in analogy with the process of deciphering a code that is composed of sugars in this case. Bacteria use fimbriae, adhesive organelles projecting from the bacterial cell, to accomplish attachment to surfaces in a carbohydrate-specific manner. The highly virulent type 1 fimbriae of uropathogenic Escherichia coli (UPEC), for example, carry an α-d-mannoside-specific lectin called FimH, which is important for the adhesive process. Today, powerful small molecule FimH antagonists have been developed that raise the hope of developing an effective antiadhesion therapy against microbial infection. However, as adhesion factors are highly redundant and cell adhesion is very complex and multifaceted, new molecular architectures such as modern glycopolymers should be considered as additional tools in deciphering the glycocode. This chapter has been written to inspire some relevant ideas.

This chapter discusses how glycopolymers might function in the context of microbial adhesion. This is an important topic as attachment of viruses and bacteria to surfaces is a global problem and for host organisms it has fundamental implications for their vitality. This was considered when the human microbiome project was launched in 2008. Consequently, the human microbiome project is dedicated to research into how changes of microbial colonization influence human health and disease.1 

It has turned out that microbial colonization of the body is largely associated with the glycoconjugate decoration of the host cells, named the ‘glycocalyx.’ The glycocalyx of a cell is an extracellular compartment comprising a huge variety of different glycoconjugates. Strikingly, it forms an anchoring platform for invading microbes. It has been asked how carbohydrate recognition has evolved among microbes,2  how it is regulated and how it develops during the lifetime of an organism, in other words, how binding to cell surface carbohydrates is being ‘spelled’ (Figure 1.1). It has been suggested that the oligo- and polysaccharide structures that are expressed on cell surfaces function in the sense of a ‘glycocode,’3  thus paralleling the biology of carbohydrates with the alphabet of a language, in order to decipher its meaning.4  Of course, it is sensible to consider the diversity of carbohydrate structures as a biologically meaningful concert corresponding to the whole of molecular interactions. Glycopolymers can be regarded as a means to interrogate a putative carbohydrate alphabet and, moreover, as a powerful tool to prevent microbial colonization of surfaces.

Figure 1.1

‘Deciphering the glycocode.’4  Cartoon to exemplify that carbohydrate-specific adhesion of, e.g., a bacterial cell to the glycocalyx of a host cell might be looked at as reading a code.

Figure 1.1

‘Deciphering the glycocode.’4  Cartoon to exemplify that carbohydrate-specific adhesion of, e.g., a bacterial cell to the glycocalyx of a host cell might be looked at as reading a code.

Close modal

To colonize cell surfaces of the host, bacteria, for example, have to accomplish a process of adhesion in order to withstand natural defence mechanisms and mechanical shear stress. Stable adhesion can lead to the formation of bacterial biofilms, which is accompanied by vital advantages for the microbial colonies5  but disadvantages for the host. Finally, adhesion apparently is a prerequisite for bacterial infections that constitute a major global health problem, in particular in developing countries. Bacterial infections are especially dangerous for newborns and young children,6  with the most common serious neonatal infections involving bacteremia, meningitis and respiratory tract infections. Key pathogens in these infections are Escherichia coli, Klebsiella sp., Staphylococcus aureus and Streptococcus pyogenes.7 

One important mechanism of bacterial adhesion is based on molecular interactions between cell surface carbohydrates of the host and specialized carbohydrate-specific bacterial proteins called adhesins or lectins. Lectins were first described at the end of the 19th century,8  when it was shown that plant lectins have the ability to agglutinate erythrocytes blood group specifically. As we know today, this is a result of a multivalent carbohydrate–lectin interaction. In 1954, Boyd and Shapleigh proposed the term lectin ‘for these and other antibody-like substances’ with blood group-specific agglutination properties.9  In the 1990s, Lis and Sharon10  suggested that ‘lectin’ should be used as a general name for all proteins of non-immune origin that possess the ability to agglutinate erythrocytes and other cell types. Early classification of lectins relied on their carbohydrate specificity. However, today lectins are grouped on the basis of their structural features and especially the relatedness of their carbohydrate binding sites, which are often called ‘carbohydrate recognition domains,’ or CRDs.11–13 

It is common knowledge today that lectins are ubiquitously spread in Nature, comprising many different functions in different organisms.14  Also, many bacteria, in particular those of the Enterobacteriaceae family, have the ability to agglutinate erythrocytes by their own lectins. This haemagglutination activity of bacteria is almost always associated with the presence of multiple filamentous protein appendages projecting from the surface of the bacteria.15  These are called fimbriae (from the Latin word for ‘thread’) and also, less correctly, pili (from the Latin word for ‘hair’) (Figure 1.2). Whereas pili are involved in gene transfer between bacteria (‘sex pili’) and flagellae have the role of sensory organelles used for moving, fimbriae serve as adhesive organelles. Fimbriae contain lectin subunits, which mediate carbohydrate-specific adhesion to cell surfaces (and also cell agglutination). Thus, bacteria utilize the sugar decoration of cells – the glycocalyx – to colonize the cell surface, wherever cells are in contact with the outside environment, as for example in the case of epithelial cells.

Figure 1.2

A majority of bacterial cells, such as E. coli, are equipped with three types of hair-like protein appendages, named pili, fimbriae and flagella. Fimbriae serve as adhesive organelles, mediating adhesion to the glycocalyx of host cells. E. coli cells are covered with several hundred copies of fimbriae of different carbohydrate specificity.

Figure 1.2

A majority of bacterial cells, such as E. coli, are equipped with three types of hair-like protein appendages, named pili, fimbriae and flagella. Fimbriae serve as adhesive organelles, mediating adhesion to the glycocalyx of host cells. E. coli cells are covered with several hundred copies of fimbriae of different carbohydrate specificity.

Close modal

Type 1 fimbriae are particularly efficient adhesion tools of bacteria to mediate the colonization of various biotic and abiotic surfaces. They are uniformly distributed on the bacterial cell surface with their length varying between 0.1 and 2 µm and a width of ∼7 nm. Since the 1970s, numerous studies have been carried out to elucidate the carbohydrate specificities of bacterial adhesion, in particular of type 1 fimbriae-mediated adhesion of E. coli.6  A key finding of this research was that the type 1 fimbrial lectin, called FimH, requires α-d-mannose and α-d-mannosides for binding. The other anomer, namely β-mannosides, cannot be complexed within the carbohydrate binding site. This knowledge suggested that type 1 fimbriated bacteria can adhere to tissues expressing glycoproteins of the high-mannose type, exposing multiple terminal α-d-mannosyl units.16  For example, urinary tract infections are caused by uropathogenic E. coli (UPEC). Type 1 fimbriae are present in at least 90% of all known UPEC strains, where they are important pathogenicity factors.6,15  Today, it is known that bacterial adhesion to the surface of urothelial cells is mediated by FimH binding to oligomannoside residues of the glycoprotein uroplakin Ia. This interaction is a prerequisite for bacterial invasion.17  Consequently, much effort has been invested in the development of potent inhibitors of type 1 fimbriae-mediated bacterial adhesion in order to prevent bacterial adhesion to mucosa and thus treat bacterial infection in an approach that has been called antiadhesion therapy.18,19 

In this context, a second feature of type 1 fimbriae-mediated bacterial adhesion that was discovered already quite early is important.16  It was found that α-d-mannosides with an aromatic aglycone moiety exhibit an improved affinity to the bacterial lectin and an enhanced potency as inhibitors of type 1 fimbriae-mediated bacterial adhesion to surfaces. Today, this finding is well understood based on the X-ray studies of the structure of the type 1 fimbrial lectin FimH that have been published since 1999.20–23  Structural biology has shown that the entrance of the carbohydrate binding site of FimH is flanked by two tyrosine residues, Y48 and Y137, which make π–π interactions with an aromatic aglycone of an α-d-mannoside ligand that is complexed within the cavity of the FimH carbohydrate binding site (Figure 1.3).

Figure 1.3

Left: spatial orientation of the amino acid residues at the entrance of the carbohydrate binding site of the bacterial lectin FimH as revealed by crystallography. The tyrosine residues Y48 and Y137 form a so-called ‘tyrosine gate’ that mediates the comparatively high affinity of mannosides with an aromatic aglycone by formation of π–π interactions. Right: the FimH carbohydrate binding site depicted as a Connolly surface, complexed with the mannoside 2 (cf.Figure 1.5). Mannoside 2 is shown as a CPK model. The large chloro substituent of 2 pointing towards the observer fills a depression at the ridge of the carbohydrate binding site, thereby improving affinity. The ring structure in white explains how α-d-mannoside ligands are located within the FimH cleft, the α-glycosidic bond sticking out of the binding site.

Figure 1.3

Left: spatial orientation of the amino acid residues at the entrance of the carbohydrate binding site of the bacterial lectin FimH as revealed by crystallography. The tyrosine residues Y48 and Y137 form a so-called ‘tyrosine gate’ that mediates the comparatively high affinity of mannosides with an aromatic aglycone by formation of π–π interactions. Right: the FimH carbohydrate binding site depicted as a Connolly surface, complexed with the mannoside 2 (cf.Figure 1.5). Mannoside 2 is shown as a CPK model. The large chloro substituent of 2 pointing towards the observer fills a depression at the ridge of the carbohydrate binding site, thereby improving affinity. The ring structure in white explains how α-d-mannoside ligands are located within the FimH cleft, the α-glycosidic bond sticking out of the binding site.

Close modal

This and other structural features of the bacterial lectin FimH have been described elsewhere6,24–26  and are not further detailed in this account. Similarly, the biosynthesis of type 1 fimbriae has been elucidated and reviewed.27,28  Briefly, the fimbrial appendage is assembled in the outer membrane of Gram-negative bacteria in a process called the chaperone–usher pathway. To be able to judge the potential value of especially glycopolymers as inhibitors of type 1 fimbriae-mediated bacterial adhesion, it is important to know that FimH is a two-domain protein, terminating every type 1 fimbrial rod (Figure 1.4). The so-called pilin domain of FimH, FimHP, is required to anchor the protein at the fimbrial tip, comprising also the subunits FimF and FimG. The lectin domain FimHL, on the other hand, accommodates the α-d-mannoside-specific carbohydrate-binding site. Both FimH domains are interconnected by a hinge region, permitting allosteric regulation of the carbohydrate binding site (see below).29,30 

Figure 1.4

Left: type 1 fimbriae are projecting from the outer membrane (OM) of Gram-negative bacteria where they are assembled in a process named the chaperone–usher pathway. The fimbrial rod is a right-handed helical structure composed of numerous FimA subunits, terminated by the fimbrial tip comprising FimF, FimG and the lectin FimH, the last mediating α-d-mannose-specific adhesion. FimH is a two-domain protein composed of a pilin and a lectin domain. Right: when shear stress is exerted, type 1 fimbriae can be elongated along the FimA helix and, in addition, FimH undergoes an allosteric rearrangement in which the lectin domain is stretched and mannose binding is enhanced concurrently. This allosteric process leading to enhanced ligand binding as a result of mechanical stress is called the ‘catch bond’ mechanism.

Figure 1.4

Left: type 1 fimbriae are projecting from the outer membrane (OM) of Gram-negative bacteria where they are assembled in a process named the chaperone–usher pathway. The fimbrial rod is a right-handed helical structure composed of numerous FimA subunits, terminated by the fimbrial tip comprising FimF, FimG and the lectin FimH, the last mediating α-d-mannose-specific adhesion. FimH is a two-domain protein composed of a pilin and a lectin domain. Right: when shear stress is exerted, type 1 fimbriae can be elongated along the FimA helix and, in addition, FimH undergoes an allosteric rearrangement in which the lectin domain is stretched and mannose binding is enhanced concurrently. This allosteric process leading to enhanced ligand binding as a result of mechanical stress is called the ‘catch bond’ mechanism.

Close modal

Based on the information obtained in structural biology studies, molecular modelling was employed to design tailor-made ligands of FimH and FimH antagonists. Synthesis and testing of these non-natural α-d-mannosides have only recently led to a revival of the idea of an antiadhesion therapy against microbial infection.31  In the 1990s, Lindhorst et al. introduced the idea of using multivalent α-d-mannoside clusters to inhibit effectively type 1 fimbriae-mediated bacterial adhesion in a potential therapeutic context.32  Later, molecular docking studies led to promising new monovalent mannosides as potent FimH antagonists.33  Many groups have added various high-affinity ligands of FimH to the arsenal of synthetic FimH antagonists with even nanomolar affinities, which is particularly potent in the context of lectin binding.34  The literature on the design and testing of FimH antagonists and inhibitors of type 1 fimbriae-mediated bacterial adhesion was reviewed in 2011.35  Since then, Ernst’s group has complemented the collection of promising FimH antagonists with new mannosides that were shown to be non-toxic and active in vivo. The best representatives have even entered clinical studies concerning their value in the treatment of cystitis.36–39 

Five key representatives of highly potent FimH ligands are illustrated in Figure 1.5. Heptyl α-d-mannoside (1) was found to possess a 440-times greater power as inhibitor of type 1 fimbriae-mediated bacterial adhesion than methyl α-d-mannoside (not shown).40  The squaric acid derivative 2 has approximately 10 times the inhibitory potency of its analogue o-chloro-p-nitrophenyl α-d-mannoside (not shown).33  The photosensitive azobenzene mannoside 3 has almost the same inhibitory power as p-nitrophenyl α-d-mannoside (not shown) but has little value as an inhibitor of bacterial adhesion in vivo owing to its limited water solubility.41,42  The respective mannobioside on the other hand, is beneficial as a water-soluble and photosensitive FimH ligand.41 

Figure 1.5

Structures of five potent representatives of small molecule FimH antagonists.

Figure 1.5

Structures of five potent representatives of small molecule FimH antagonists.

Close modal

The biphenyl mannosides 4 and 5 are the result of recent systematic lead optimization.37,43  Ernst and co-workers determined the KD values of 1 and 4, among others, by an in-solution affinity assay as KD (1) = 5.6 ± 1.6 nM and KD (4) = 0.71 ± 0.01 nM.39  Indolylphenyl and indolinylphenyl mannosides have also been added to the collection of potent FimH antagonists.38  Testing of the most potent indolinylphenyl mannoside 6 revealed that the administration of a low dosage such as 1 mg kg−1 (corresponding to approximately 25 µg per mouse) was sufficient to prevent urinary tract infection in mice for more than 8 h.38  Bacterial colonization of the bladder could be reduced by almost four orders of magnitude, comparable to a standard antibiotic treatment. Hence the vision of an antiadhesion therapy to complement antibiotic treatment, which currently struggles with antibiotic resistance, becomes realistic.

Without doubt, multivalency of molecular interactions is an important factor in carbohydrate recognition. Numerous multivalency effects have been observed in the glycosciences and interpreted according to various models.44–48  Lee and Lee were the first to observe a multivalency effect in lectin binding employing relatively small di- and trivalent cluster glycosides and coined the term ‘cluster effect’ for the observations made.49,50  At the time, they concluded that multivalent carbohydrate binding sites occur in lectins, but when the multivalency of lectin CRDs became more and more obvious based on many crystal structures, researchers became especially interested in the design of multivalent glycomimetics to produce highly potent lectin ligands or inhibitors of lectin-mediated cellular adhesion. Among others, multivalent glycomimetics based on non-carbohydrate polymer scaffolds were launched and named ‘glycopolymers’ to distinguish them from natural polysaccharides.51  Roy and Kiessling and their colleagues were early pioneers in the field,52,53  but more recently modern polymer chemistry has further stimulated the synthesis and application of glycopolymers.54 

Thus, glycopolymers may also be designed to inhibit fimbriae-mediated bacterial adhesion. In spite of the fact that the type 1 fimbrial lectin FimH is an explicitly monovalent lectin, multivalent mannosides have shown favourable effects as inhibitors of type 1 fimbriae-mediated bacterial adhesion.35  Such findings might be due to statistical effects on the one hand, taking advantage of the dense packing of mannoside ligands in close proximity to one FimH carbohydrate binding site. On the other hand, appropriately dimensioned multivalent mannosides could also lead to simultaneous binding of multiple FimH units on multiple (∼100–400 per bacterial cell) copies of type 1 (Figure 1.6).

Figure 1.6

Glycopolymers equipped with specific carbohydrate residues (e.g. α-d-mannosyl units) could interact with, for instance, type 1-fimbriated bacteria in a multivalent fashion to effect a general deprivation of adhesive ability.

Figure 1.6

Glycopolymers equipped with specific carbohydrate residues (e.g. α-d-mannosyl units) could interact with, for instance, type 1-fimbriated bacteria in a multivalent fashion to effect a general deprivation of adhesive ability.

Close modal

Certainly, multivalent binding of glycopolymers to fimbriated bacteria or other microbes, that adhere carbohydrate-specifically, is not per se effective as the entropic penalty that can occur upon fixation of the formerly flexible polymer on the bacterial surface might prevent high-affinity binding. However, based on modern polymer chemistry, this problem could be circumvented. Thus, appropriately ‘encoded’ glycopolymer inhibitors of microbial adhesion to surfaces could indeed be provided as powerful tools for various different applications.

For the systematic fabrication of antiadhesive glycopolymers the principal design outlined in Figure 1.7 can be envisaged. According to this approach, a polymer backbone can be designed with desired hydrophobicity, steric and conformational properties and carrying appropriate functional groups to allow selective attachment of carbohydrate moieties. Ideally, the attachment chemistry should work according to the concept of ‘click chemistry,55  but more classical ligation methods could also be employed. For the fabrication of antiadhesive glycoarrays, we and others have often used a collection of functionalized glycosides that can be easily ligated to prefunctionalized surfaces.56–59  Similar mannosides (cf.Figure 1.7) could be employed to produce glycopolymers that inhibit type 1 fimbriae-mediated adhesion, for example. Alkyne–azide cycloaddition,60  triol–ene reactions,61  peptide coupling62  and thiourea bridging63  are approved methods to ligate carbohydrates to molecular scaffolds, and even bioorthogonal chemistry64  is certainly amenable to the synthesis of glycopolymers.

Figure 1.7

Functionalized polymers can be ligated to functional glycosides, e.g., mannosides, to yield antiadhesive glycopolymers. A series of known α-d-mannosides are depicted, permitting easy ligation with appropriately functionalized polymers, such as alkyne–azide cycloaddition, thiol–ene reaction, peptide coupling or thiourea bridging. The ligated glycosides might be regarded as ‘letters’ and, to take the metaphor further, a resulting glycopolymer might be interpreted as a ‘sentence.’

Figure 1.7

Functionalized polymers can be ligated to functional glycosides, e.g., mannosides, to yield antiadhesive glycopolymers. A series of known α-d-mannosides are depicted, permitting easy ligation with appropriately functionalized polymers, such as alkyne–azide cycloaddition, thiol–ene reaction, peptide coupling or thiourea bridging. The ligated glycosides might be regarded as ‘letters’ and, to take the metaphor further, a resulting glycopolymer might be interpreted as a ‘sentence.’

Close modal

A number of structural parameters are known to influence and direct multivalent carbohydrate–lectin interactions and cell adhesion. For example, the density of carbohydrate ligands can be influential.65,66  Moreover, the complexity of carbohydrate decoration and in particular clustering of glycosides of different nature have been found to improve ligand binding in many cases. The latter observation has been described as the ‘heteroglycocluster effect’.67  All of these aspects of carbohydrate recognition could be studied and adjusted with the aid of glycopolymers, as outlined in Figure 1.8.

Figure 1.8

Structural parameters of glycopolymers (A) can be varied. Carbohydrate density can be influenced and varied according to cartoon B or by conjugation of cluster glycosides instead of simple monosaccharides (C). Heteroglycopolymers (D) can be achieved through an orthogonal ligation approach.

Figure 1.8

Structural parameters of glycopolymers (A) can be varied. Carbohydrate density can be influenced and varied according to cartoon B or by conjugation of cluster glycosides instead of simple monosaccharides (C). Heteroglycopolymers (D) can be achieved through an orthogonal ligation approach.

Close modal

With regard to inhibition of type 1 fimbriae-mediated bacterial adhesion, the identified high-performance FimH antagonists 16 (Figure 1.5) can be easily ligated to functionalized polymers either directly or after the introduction of a suitable linker. Some practical ideas are depicted in Figure 1.9. The mercapto-functionalized azobenzene mannoside 9, for example, has recently been used for the fabrication of photoswitchable carbohydrate-decorated self-assembled monolayers on gold, so-called glyco-SAMs.68  The same molecule can be utilized to make photosensitive glycopolymers, in which reversible EZE isomerization of the azobenzene NN double bond might be used to modulate the antiadhesive power of the respective polymer.69 

Figure 1.9

The potent FimH antagonists 16 (cf. Figure 1.5) can be used as antiadhesive carbohydrate ‘letters’ for the fabrication of glycopolymers either directly or after facile conversion into derivatives such as 711.

Figure 1.9

The potent FimH antagonists 16 (cf. Figure 1.5) can be used as antiadhesive carbohydrate ‘letters’ for the fabrication of glycopolymers either directly or after facile conversion into derivatives such as 711.

Close modal

Equally, the recently introduced70  ‘dual click’ approach for glyco-SAM production can enrich the field of glycopolymer synthesis (Figure 1.10). For biological adhesion studies, it is essential to use biorepulsive moieties to suppress the non-specific adsorption of proteins on a surface. Such protein-repelling properties are mediated by oligoethylene glycol (OEG) linkers, which can be introduced to a functionalized scaffold or surface by a first ‘click reaction.’ A second ‘click reaction’ allows the attachment of a carbohydrate head group, such as an α-d-mannoside, at the terminal end of the molecular construct. This ‘dual click’ concept has been demonstrated to be viable by systematic step-by-step assembly of glyco-SAMs and their testing as (anti)adhesive surfaces using fluorescent E. coli bacteria and fluorescence read-out.

Figure 1.10

The ‘dual click’ approach described for the construction of glyco-SAMs,70  could be applied in glycopolymer synthesis. An oligoethylene glycol moiety, introduced in an alkyne–azide cycloaddition (‘click’ 1) adds ‘biorepulsive’ properties (inertness) to the molecule, then thiourea bridging employing NCS-functionalized sugars (‘click’ 2) adds specificity for lectin binding. By adhesion of fluorescent E. coli, the success of this approach can be proven.

Figure 1.10

The ‘dual click’ approach described for the construction of glyco-SAMs,70  could be applied in glycopolymer synthesis. An oligoethylene glycol moiety, introduced in an alkyne–azide cycloaddition (‘click’ 1) adds ‘biorepulsive’ properties (inertness) to the molecule, then thiourea bridging employing NCS-functionalized sugars (‘click’ 2) adds specificity for lectin binding. By adhesion of fluorescent E. coli, the success of this approach can be proven.

Close modal

Certainly, the use of glycopolymers in a therapeutic context, such as in antiadhesion therapy, is associated not only with potential advantages but also with risks that have to be taken seriously. As suggested in Figure 1.6, a cell could be completely knocked out by a large glycopolymer covering large parts of its surface. Physiological carbohydrate–protein interactions would then likewise be prevented. Although prevention of adhesion of pathogenic microbes is desired, inhibition of vital carbohydrate–protein and also carbohydrate–carbohydrate interactions would be highly toxic. In addition, gelation effects or haemagglutination could occur when glycopolymers are applied, which are certainly also undesired effects, especially in in vivo situations.

However, glycopolymers could find other fields of application. Instead of an intake (e.g. orally) of glycopolymers to treat patients, surface treatment of, for example, the skin can also be considered. Other areas of application concern environmentally benign prevention of biofouling or impregnation of medical surfaces that are prone to bacterial colonization.

Finally, glycopolymers could be a means to tackle the problem of redundancy in adhesion. In fact, there are many more factors than type 1 fimbriae that facilitate adhesion of microbial cells. Additional fimbriae with different carbohydrate specificities are expressed on bacteria supporting bacterial adhesion, such as the galactose-specific P-fimbriae. Possession of multiple adhesins and mechanisms of attachment is common for bacteria, permitting binding to multiple targets on a single cell. The variety of factors can cooperate to increase cellular entry, as exemplified by Neisseria meningitidis.71  Here, complex, multifunctional glycopolymers could provide powerful tools to cope with redundancy in adhesion (Figure 1.11).

Figure 1.11

Tailor-made multifunctional glycopolymers of sophisticated complexity could provide powerful tools to cope with redundancy in microbial adhesion. The cartoon suggests some structural variations to be implemented into glycopolymers that could cooperate in a specific antiadhesion approach (cf. Figures 1.6 and 1.8).

Figure 1.11

Tailor-made multifunctional glycopolymers of sophisticated complexity could provide powerful tools to cope with redundancy in microbial adhesion. The cartoon suggests some structural variations to be implemented into glycopolymers that could cooperate in a specific antiadhesion approach (cf. Figures 1.6 and 1.8).

Close modal

Furthermore, glycopolymers could even present dynamic advantages connected with bacterial adhesion by general steric hindrance of the adhesion process. In addition to the translational flexibility of bacterial cells, kinetic motion of fimbriae has to be considered, and also their conformational flexibility, and moreover, functional flexibility of the adhesive properties due to mutations and conformational flexibility of the actual lectin are important factors in bacterial adhesion. In the case of type 1 fimbriae, a so-called ‘catch bond’ mechanism72  has been discovered (see earlier), that enables bacteria to withstand mechanical force. When shear stress is applied to bacteria, an allosteric rearrangement is initiated that is mediated between the FimH domains FimHP and FimHL (cf. Figure 1.4, right). Thus, tightening of the mannose binding pocket at the far end of the lectin domain FimHL is effected. This leads to a high-affinity state of the lectin and longer lived interactions with mannoside ligands.29,30  The observation that the lifetimes of some biological adhesive bonds are enhanced by tensile mechanical force certainly has important implications for inhibition of bacterial adhesion and engineering of antiadhesives.

Carbohydrate-specific adhesion of microbes to their host cells is often a prelude to cellular invasion, tissue penetration and disease. In the last two decades, considerable progress has been made in the development of inhibitors of adhesion, such as in case of small molecule FimH antagonists. Hence today, it appears realistic that urinary tract infections that are caused by adhesive E. coli bacteria (UPEC) will soon be treated by an antiadhesion therapy, applying carbohydrate inhibitors of the lectin-mediated adhesion process. However, microbial adhesion is a complex process, involving multiple adhesins and adhesive mechanisms. Therefore, there is still a need for molecular architectures that bear the conceptual flexibility to cope with the complex code that is hidden in carbohydrate–lectin and host–pathogen interactions. In this chapter, some ideas have been highlighted for the use of modern concepts of glycopolymer synthesis in the context of microbial adhesion. In this approach, small molecule lectin ligands could be applied as molecular ‘letters’ of an antiadhesive glycopolymer code.

1.
Cho
 
I.
Blaser
 
M. J.
Nat. Rev. Genet.
2012
, vol. 
13
 pg. 
260
 
2.
Varki
 
A.
J. Mol. Med.
2012
, vol. 
90
 pg. 
481
 
3.
Gabius
 
H.-J.
André
 
S.
Jiménez-Barbero
 
J.
Romero
 
A.
Solís
 
D.
Trends Biochem. Sci.
2011
, vol. 
36
 pg. 
298
 
4.
Feizi
 
T.
Chai
 
W.
Nat. Rev. Mol. Cell Biol.
2004
, vol. 
5
 pg. 
582
 
5.
O'Toole
 
G.
Kaplan
 
H. B.
Kolter
 
R.
Annu. Rev. Microbiol.
2000
, vol. 
54
 pg. 
49
 
6.
Knight
 
S. D.
Bouckaert
 
J.
Top. Curr. Chem.
2009
, vol. 
288
 pg. 
67
 
7.
Osrin
 
D.
Vergnano
 
S.
Costello
 
A.
Curr. Opin. Infect. Dis.
2004
, vol. 
17
 pg. 
217
 
8.
Sharon
 
N.
Lis
 
H.
Glycobiology
2004
, vol. 
14
 pg. 
53R
 
9.
Boyd
 
W. C.
Shapleigh
 
E.
Science
1954
, vol. 
119
 pg. 
419
 
10.
Lis
 
H.
Sharon
 
N.
Chem. Rev.
1998
, vol. 
98
 pg. 
637
 
11.
Ambrosi
 
M.
Cameron
 
N. R.
Davis
 
B. G.
Org. Biomol. Chem.
2005
, vol. 
3
 pg. 
1593
 
12.
Drickamer
 
K.
Curr. Opin. Struct. Biol.
1993
, vol. 
3
 pg. 
393
 
13.
Dodd
 
R. B.
Drickamer
 
K.
Glycobiology
2001
, vol. 
11
 pg. 
71R
 
14.
Ohlsen
 
K.
Oelschlaeger
 
T.
Hacker
 
J.
Khan
 
A. S.
Top. Curr. Chem.
2009
, vol. 
288
 pg. 
109
 
15.
Sharon
 
N.
FEBS Lett.
1987
, vol. 
217
 pg. 
145
 
16.
Martinez
 
J. J.
Mulvey
 
M. A.
Schilling
 
J. D.
Pinkner
 
J. S.
Hultgren
 
S. J.
EMBO J.
2000
, vol. 
19
 pg. 
2803
 
17.
Ronald
 
A.
Am. J. Med.
2002
, vol. 
113
 pg. 
14S
 
18.
Pieters
 
R. J.
Med. Res. Rev.
2007
, vol. 
27
 pg. 
796
 
19.
Ofek
 
I.
Hasty
 
D. L.
Sharon
 
N.
FEMS Immunol. Med. Microbiol.
2003
, vol. 
38
 pg. 
181
 
20.
Choudhury
 
D.
Thompson
 
A.
Stojanoff
 
V.
Langerman
 
S.
Pinkner
 
J.
Hultgren
 
S. J.
Knight
 
S.
Science
1999
, vol. 
285
 pg. 
1061
 
21.
Hung
 
C. S.
Bouckaert
 
J.
Hung
 
D.
Pinkner
 
J.
Widberg
 
C.
Defusco
 
A.
Auguste
 
C. G.
Strouse
 
R.
Langermann
 
S.
Waksman
 
G.
Hultgren
 
S. J.
Mol. Microbiol.
2002
, vol. 
44
 pg. 
903
 
22.
Bouckaert
 
J.
Mackenzie
 
J.
de Paz
 
J. L.
Chipwaza
 
B.
Choudhury
 
D.
Zavialov
 
A.
Mannerstedt
 
K.
Anderson
 
J.
Piérard
 
D.
Wyns
 
L.
Seeberger
 
P. H.
Oscarson
 
S.
De Greve
 
H.
Knight
 
S. D.
Mol. Microbiol.
2006
, vol. 
61
 pg. 
1556
 
23.
Wellens
 
A.
Garofalo
 
C.
Nguyen
 
H.
Van Gerven
 
N.
Slättegård
 
R.
Hernalsteens
 
J. P.
Wyns
 
L.
Oscarson
 
S.
De Greve
 
H.
Hultgren
 
S.
Bouckaert
 
J.
PLoS One
2008
, vol. 
3
 pg. 
e2040
 
24.
T. K.
Lindhorst
, in:
Synthesis and Biological Applications of Glycoconjugates
, ed. O. Renaudet, N. Spinelli,
Bentham eBooks
,
Sharjah
,
2011
, pp. 12–35
25.
Schwartz
 
D. J.
Kalas
 
V.
Pinkner
 
J. S.
Chen
 
S. L.
Spaulding
 
C. N.
Dodson
 
K. W.
Hultgren
 
S. J.
Proc. Natl. Acad. Sci. U. S. A.
2013
, vol. 
110
 pg. 
15530
 
26.
Phan
 
G.
Remaut
 
H.
Wang
 
T.
Allen
 
W. J.
Pirker
 
K. F.
Lebedev
 
A.
Henderson
 
N. S.
Geibel
 
S.
Volkan
 
E.
Yun
 
J.
Kunze
 
M. B. A.
Pinkner
 
J. S.
Ford
 
B.
Kay
 
C. W. M.
Li
 
H.
Hultgren
 
S. J.
Thanassi
 
D. G.
Waksman
 
G.
Nature
2011
, vol. 
474
 pg. 
49
 
27.
Waksman
 
G.
Hultgren
 
S. J.
Nat. Rev. Microbiol.
2009
, vol. 
7
 pg. 
765
 
28.
Crespo
 
M. D.
Puorger
 
C.
Schärer
 
M. A.
Eidam
 
O.
Grütter
 
M. G.
Capitani
 
G.
Glockshuber
 
R.
Nat. Chem. Biol.
2012
, vol. 
8
 pg. 
707
 
29.
Le Trong
 
I.
Aprikian
 
P.
Kidd
 
B. A.
Forero-Shelton
 
M.
Tchesnokova
 
V.
Rajagopal
 
P.
Rodgriguez
 
V.
Interlandi
 
G.
Klevit
 
R.
Vogel
 
V.
Stenkamp
 
R. E.
Sokurenko
 
E. V.
Thomas
 
W. E.
Cell
2010
, vol. 
141
 pg. 
645
 
30.
Aprikian
 
P.
Interlandi
 
G.
Kidd
 
B.
Le Trong
 
I.
Tchesnokova
 
V.
Yakovenko
 
O.
Whitfield
 
M.
Bullitt
 
E.
Stenkamp
 
R.
Thomas
 
W. E.
Sokurenko
 
E. V.
PLoS Biol.
2011
, vol. 
9
 pg. 
e1000617
 
31.
Silverman
 
J. A.
Schreiber 4th
 
H. L.
Hooton
 
T. M.
Hultgren
 
S. J.
Curr. Urol. Rep.
2013
, vol. 
14
 pg. 
448
 
32.
Lindhorst
 
T. K.
Kieburg
 
C.
Krallmann-Wenzel
 
U.
Glycoconjugate J.
1998
, vol. 
15
 pg. 
605
 
33.
Sperling
 
O.
Fuchs
 
A.
Lindhorst
 
T. K.
Org. Biomol. Chem.
2006
, vol. 
4
 pg. 
3913
 
34.
Lemieux
 
R. U.
Acc. Chem. Res.
1996
, vol. 
29
 pg. 
373
 
35.
Hartmann
 
M.
Lindhorst
 
T. K.
Eur. J. Org. Chem.
2011
pg. 
3583
 
36.
Ernst
 
B.
Magnani
 
J. L.
Nat. Rev. Drug Discovery
2009
, vol. 
8
 pg. 
661
 
37.
Pang
 
L.
Kleeb
 
S.
Lemme
 
K.
Rabbani
 
S.
Scharenberg
 
M.
Zalewski
 
A.
Schädler
 
F.
Schwardt
 
O.
Ernst
 
B.
ChemMedChem
2012
, vol. 
7
 pg. 
1404
 
38.
Xiaohua
 
J.
Abgottspon
 
D.
Kleeb
 
S.
Rabbani
 
S.
Scharenberg
 
M.
Wittwer
 
M.
Haug
 
M.
Schwardt
 
O.
Ernst
 
B.
J. Med. Chem.
2012
, vol. 
55
 pg. 
4700
 
39.
Scharenberg
 
M.
Xiaohua
 
J.
Pang
 
L.
Navarra
 
G.
Rabbani
 
S.
Binder
 
F.
Schwardt
 
O.
Ernst
 
B.
ChemMedChem
2014
, vol. 
9
 pg. 
78
 
40.
Bouckaert
 
J.
Berglund
 
J.
Schembri
 
M.
Genst
 
E. D.
Cools
 
L.
Wuhrer
 
M.
Hung
 
C.-S.
Pinkner
 
J.
Slättegård
 
R.
Zavialov
 
A.
Choudhury
 
D.
Langermann
 
S.
Hultgren
 
S. J.
Wyns
 
L.
Klemm
 
P.
Oscarson
 
S.
Knight
 
S. D.
Greve
 
H. D.
Mol. Microbiol.
2005
, vol. 
55
 pg. 
441
 
41.
Chandrasekaran
 
V.
Kolbe
 
K.
Beiroth
 
F.
Lindhorst
 
T. K.
Beilstein J. Org. Chem.
2013
, vol. 
9
 pg. 
223
 
42.
Hartmann
 
M.
Papavlassopoulos
 
H.
Chandrasekaran
 
V.
Grabosch
 
C.
Beiroth
 
F.
Lindhorst
 
T. K.
Röhl
 
C.
FEBS Lett.
2012
, vol. 
586
 pg. 
1459
 
43.
Han
 
Z.
Pinkner
 
J. S.
Ford
 
B.
Chorell
 
E.
Crowley
 
J. M.
Cusumano
 
C. K.
Campbell
 
S.
Henderson
 
J. P.
Hultgren
 
S. J.
Janetka
 
J. W.
J. Med. Chem.
2012
, vol. 
55
 pg. 
3945
 
44.
Christensen
 
T.
Gooden
 
D. M.
Kung
 
J. E.
Toone
 
E. J.
J. Am. Chem. Soc.
2003
, vol. 
125
 pg. 
7357
 
45.
Lahmann
 
M.
Top. Curr. Chem.
2009
, vol. 
288
 pg. 
17
 
46.
Kiessling
 
L. L.
Gestwicki
 
J. E.
Strong
 
L. E.
Angew. Chem. Int. Ed.
2006
, vol. 
45
 pg. 
2348
 
Angew. Chem.
2006
, vol. 
118
 pg. 
2408
 
47.
Mammen
 
M.
Choi
 
S.-K.
Whitesides
 
G. M.
Angew. Chem. Int. Ed.
1998
, vol. 
37
 pg. 
2754
 
Angew. Chem.
1998
, vol. 
110
 pg. 
2908
 
48.
Chabre
 
Y. M.
Roy
 
R.
Adv. Carbohydr. Chem. Biochem.
2010
, vol. 
63
 pg. 
165
 
49.
Lee
 
R. T.
Lee
 
Y. C.
Carbohydr. Res.
1974
, vol. 
37
 pg. 
193
 
50.
Lee
 
Y. C.
Lee
 
R. T.
Acc. Chem. Res.
1995
, vol. 
28
 pg. 
321
 
51.
Voit
 
B.
Appelhans
 
D.
Macromol. Chem. Phys.
2010
, vol. 
211
 pg. 
727
 
52.
Baek
 
M.-G.
Roy
 
R.
Biomacromolecules
2000
, vol. 
1
 pg. 
768
 
53.
Kiessling
 
L. L.
Grim
 
J. C.
Chem. Soc. Rev.
2013
, vol. 
42
 pg. 
4476
 
54.
Ponader
 
D.
Maffre
 
P.
Aretz
 
J.
Pussak
 
D.
Ninnemann
 
N. M.
Schmidt
 
S.
Seeberger
 
P. H.
Rademacher
 
C.
Nienhaus
 
G. U.
Hartmann
 
L.
J. Am. Chem. Soc.
2014
, vol. 
136
 pg. 
2008
 
55.
Kolb
 
H. C.
Finn
 
M. G.
Sharpless
 
K. B.
Angew. Chem. Int. Ed.
2001
, vol. 
40
 pg. 
2004
 
Angew. Chem.
2001
, vol. 
113
 pg. 
2056
 
56.
Hartmann
 
M.
Betz
 
P.
Sun
 
Y.
Gorb
 
S. N.
Lindhorst
 
T. K.
Krueger
 
A.
Chem. Eur. J.
2012
, vol. 
13
 pg. 
6485
 
57.
Weissenborn
 
M. J.
Castangia
 
R.
Wehner
 
J. W.
Lindhorst
 
T. K.
Flitsch
 
S. L.
Chem. Commun.
2012
, vol. 
48
 pg. 
4444
 
58.
Wehner
 
J. W.
Weissenborn
 
M. J.
Hartmann
 
M.
Gray
 
C. J.
Šardzík
 
R.
Eyers
 
C. E.
Flitsch
 
S. L.
Lindhorst
 
T. K.
Org. Biomol. Chem.
2012
, vol. 
10
 pg. 
8919
 
59.
Hartmann
 
M.
Horst
 
A. K.
Klemm
 
P.
Lindhorst
 
T. K.
Chem. Commun.
2010
, vol. 
46
 pg. 
330
 
60.
Tornøe
 
C. W.
Christensen
 
C.
Meldal
 
M.
J. Org. Chem.
2002
, vol. 
67
 pg. 
3057
 
61.
Dondoni
 
A.
Marra
 
A.
Chem. Soc. Rev.
2012
, vol. 
41
 pg. 
573
 
62.
Liu
 
J.
Gray
 
W. D.
Davis
 
M. E.
Luo
 
Y.
Interface Focus
2012
, vol. 
2
 pg. 
307
 
63.
Martínez
 
Á.
Ortiz Mellet
 
C.
García Fernández
 
J. M.
Chem. Soc. Rev.
2013
, vol. 
42
 pg. 
4746
 
64.
Sletten
 
E. M.
Bertozzi
 
C.
Acc. Chem. Res.
2011
, vol. 
44
 pg. 
666
 
65.
Wehner
 
J. W.
Hartmann
 
M.
Lindhorst
 
T. K.
Carbohydr. Res.
2013
, vol. 
371
 pg. 
22
 
66.
Deeg
 
J. A.
Louban
 
I.
Aydin
 
D.
Selhuber-Unkel
 
C.
Kessler
 
H.
Spatz
 
J. P.
Nano Lett.
2011
, vol. 
11
 pg. 
1469
 
67.
Jiménez Blanco
 
J. L.
Ortiz Mellet
 
C.
García Fernández
 
J. M.
Chem. Soc. Rev.
2013
, vol. 
42
 pg. 
4518
 
68.
Chandrasekaran
 
V.
Jacob
 
H.
Petersen
 
F.
Kathirvel
 
K.
Tuczek
 
F.
Lindhorst
 
T. K.
Chem. Eur. J.
2014
, vol. 
20
 pg. 
8744
 
69.
Weber
 
T.
Chandrasekaran
 
V.
Stamer
 
I.
Thygesen
 
M. B.
Terfort
 
A.
Lindhorst
 
T. K.
Angew. Chem. Int. Ed.,
2014
, vol. 
53
 pg. 
14583
 
Angew. Chem.
2014
, vol. 
126
 pg. 
14812
 
70.
Grabosch
 
C.
Kind
 
M.
Gies
 
Y.
Schweighöfer
 
F.
Terfort
 
A.
Lindhorst
 
T. K.
Org. Biomol. Chem.
2013
, vol. 
11
 pg. 
4006
 
71.
Virji
 
M.
Top. Curr. Chem.
2009
, vol. 
288
 pg. 
1
 
72.
Thomas
 
W.
Annu. Rev. Biomed. Eng.
2008
, vol. 
10
 pg. 
39
 
Close Modal

or Create an Account

Close Modal
Close Modal