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1 (REF. 104, 106)
7 (REF. 115) 8 (REF. 110) 9 (REF. 114) 10 (REF. 117)
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2 (REF. 109)
3 (REF. 116)
Structural exploration
4 (REF. 108)
Prodrug strategyNew frontiers
5 R = Me (Prodrug)
6 R = Na (active principle)
(REF. 111)
Core structure
“Drug-like” properties
(PK/PD optimization)
Figure5.8 Structures of potent FimH antagonists and representative optimization strategies.
e.g. Target-directed
combinatorial library
(REF. 117)
FimH
5.3 The Bacterial Adhesin FimH
derivatives (→ 3) and on the basis of various crystal structures (PDB code: 4AV5[103],
3MCY[108], 4CST[110], and 4CSS[110]) with biphenyl mannosides (→ 4, 8), indicating the positive effect of π–π stacking with the amino acid side chains of Tyr48 and
Tyr137 of the “tyrosine gate.” Furthermore, a favorable effect of ortho-substitution on
the aromatic ring adjacent to the anomeric center of up to a factor 10was reported by
several groups (→ 2, 5, and 6)[109, 111].
Further studies on FimH antagonists with extended aromatic moieties lead to a
series of modified biphenyl (→ 4-6, 8, 9)[108, 110–114], indolinylphenyl (→ 7)[115],
squaric acid derivatives (→ 3)[116], and pyrrolylphenyl (→ 10)[117], all showing
the affinities in low nanomolar range and oral availability.
For successful clinical applications of FimH antagonists, oral bioavailability and
fast renal excretion for reaching the targets in the urinary tract are prerequisites. In
2010, Klein etal. reported both the invitro and invivo PK data of a series of biphenyl
α--mannosides [111]. Because intestinal absorption and renal elimination are
related to opposed properties, i.e. lipophilicity for intestinal absorption and hydrophilicity for renal elimination, a prodrug approach was applied to meet both conditions. For example, after high intestinal absorption, the ester (→ 5) is hydrolzed by
esterases in the enterocytes and in the liver (“first pass”) releases the acid (→ 6),
which undergoes fast renal elimination to reach the target in the bladder, where it
realizes the therapeutic effect. Later structural modifications on FimH antagonists,
such as the indolinylphenyl derivative (→ 7)[115] or bioisosteric replacement of the
carboxylate [110], improved oral bioavailability in vivo. Among these modified
structures, the indolinylphenyls showed a high therapeutic potential, resulting from
optimized PK properties, and a substantial reduction of the dosage, i.e. a successful
1
treatment of UTI with a low dosage of 1 mg kg
without any additional administration of antibiotics. However, a major drawback of these indolinylphenyl antagonists
is their low solubility, limiting their further invivo applications. Therefore, a balance between solubility and permeability is another challenge for reaching oral bioavailability. Structural modifications, such as disruption of the molecular planarity
and introduction of heteroatoms, provided promising solutions to fulfill this criterion [117]. Finally, FimH antagonist GSK3882347 (structure not disclosed) has
already entered Phase I clinical study (NCT04488770) in a collaboration between
Fimbrion Therapeutics and GlaxoSmithKline.
147
5.3.4 Conclusion and Perspectives
Diverse strategies, besides traditional chemical synthesis in situ target-directed
dynamic combinatorial chemistry (Figure 5.8, New Frontiers) [107], were implemented in the search for high-potency FimH antagonists. Besides low-molecularweight antagonists, carbohydrate-based clusters of mannosides [118–122] and
carbohydrate dendrimers [123–126] were synthesized and extensively studied for
FimH inhibition[127]. Although these multivalent mannosides have shown high
potency, their sizes, polarity, and possible induction of gelation effects or hemagglutination invivo make therapeutic application unlikely.
5 Antiadhesive Carbohydrates and Glycomimetics
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148
To summarize, in vitro and invivo functionally active mannosides block UPEC
adhesion through high-affinity binding to the mannose-binding site of FimH, thus
preventing bacterial colonization on urinary tract surfaces. Over the last decade, our
knowledge of FimH binding has been immensely expanded, thus facilitating the
rational design of FimH antagonists with diverse structural complexity. Structural
optimization for FimH antagonists has focused on improving pharmacokinetic and
pharmacodynamic properties, aiming at invivo potency and oral bioavailability.
Ideally, after oral administration, the mannosides, which are characterized by acid
stability in the stomach, will be quickly absorbed in the intestine and, once systemically available, will not be metabolized but rapidly eliminated by the kidney to reach
their therapeutic target, the type 1 pili in the bladder and urinary tract. Encouragingly,
some mouse models demonstrated that oral administration of the mannosides (→ 5,
7, 8, and 9) prevented UPEC colonization in the bladder in both acute and chronic
UTIs[110, 111, 114, 115]. Additionally, biphenyl mannoside (→ 6) has shown inhibitory potency on biofilm formation in vitro [114]. Recent research revealed that
FimH adhesins act synergistically with PapG-II adhesins–another virulence factor
prevalently expressed among the strains of UPEC causing pyelonephritis [128].
Therefore, in order to combat arising antibiotic resistance, combining both FimH
and PapG antagonists could lead to a more effective treatment for UTIs[129, 130].
5.4 Pseudomonas aeruginosa Virulence Factors
(PA-IL and PA-IIL)
5.4.1 Introduction
P. aeruginosa is an opportunistic Gram-negative pathogen that is part of the normal
flora in healthy adults. However, it can become lethally pathogenic in immunecompromised patients [131]. P. aeruginosa is involved in both acute and chronic
infections, especially in cystic fibrosis patients[131, 132]. The therapeutic options
for these infections remain limited because this pathogen exhibits increasing resistance to many antibiotics[133]. P. aeruginosa utilizes lectins and adhesins, exposed
on pili or flagella, for anchoring to the host cells. The soluble lectins PA-IL (or LecA)
and PA-IIL (or LecB) are expressed by P. aeruginosa, specifically binding to galacto-
sides and fucosides, respectively [27, 134, 135]. Both lectins are virulence factors
under quorum-sensing control but are, by themselves, cytotoxic to primary epithelial cells[136]. Natively, PA-IL binds to α-galactosylated glycosphingolipids in lung
epithelial cell membranes, while PA-IIL interacts with fucosylated and manno-
a
sylated epitopes but preferentially with Lewis
oligosaccharides[137]. In a murine
pneumonia model, both galactose and fucose reduced infection spread[138]. It was
also reported that human milk oligosaccharides significantly prevent adhesion of
P. aeruginosa to human respiratory epithelial cells[139]. In addition, a case report
described that combination therapy of tobramycin with both -galactose and
-fucose successfully cured an 18-month-old infant with systemic and pulmonary
infections caused by tobramycin-resistant P. aeruginosa[140]. Given an increasing
(a) (b)
Figure5.9 Crystal structures of PA-IL and PA-IIL in complex with d-galactose and l-fucose,
respectively. (a) Binding sites of galactophilic lectin PA-IL complexed with d-galactose (PDB
code: 1OKO). Source: Adapted from Cioci etal.[135]. (b) Binding sites of l-fucose-binding
lectin PA-IIL complexed with l-fucose (PDB code: 1GZT). Source: Adapted from Mitchell
etal.[27].
percentage of antibiotic resistance, antiadhesive strategy alone or in combination
with antibiotics are expected to provide more effective clinical treatment to patients
suffering P. aeruginosa infections[141, 142].
2+
Both PA-IL and PA-IIL are tetrameric lectins that require Ca
ion for carbohy-
drate binding. PA-IL preferentially binds to terminal α--galactose in the presence
2+
of a bridging Ca
whereas PA-IIL binds unusually strongly (K
involvement of two Ca
ion in the CRD with a KD of 87.5 μM (Figure 5.9a) [135, 143],
: 625 nM) [144] to -fucose with the
2+
ions (Figure5.9b)[27].
D
1495.4 Pseudomonas aeruginosa Virulence Factors (PA-IL and PA-IIL)
5.4.2 Mono- and Oligovalent Glycomimetic PL-Ligands
In nature, PA-IL displays high binding affinity toward α-linked galactosides, whereas
studies with synthetic glycomimetics demonstrated its binding preference for β-aryl
galactosides (Figures 5.10, 5.1 and 5.2) [145, 146]. Aromatic aglycones establish
favorable contacts within the CRD, e.g. the 2-naphthyl moiety forms a CH–π
“T-shape” interaction with His50, contributing to improved binding affinity[145].
When the aromatic aglycone of ligand 2 was presented tetravalently, even
nanomolar affinity could be determined by ITC (→ 3, Figure5.10)[147]. Diversified
multivalent scaffolds, such as tetravalent glycopeptide, glycoclusters of various
sizes, fullerene, and gold nanoparticles, have been introduced and evaluated[34].
To date, a rationally designed divalent galactoside (→ 4, Figure5.10) with a K
28 nM toward PA-IL has proven to be the ligand with the highest binding affinity so
far[148]. Another 1,3-alternated galactosylated glycocluster (→ 5, Figure5.10) with
of 176 nM against LecA has shown almost complete protection against
a K
D
D
of
1 (REF. 145)
5 (REF. 149)
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2 (REF. 146)
4 (REF. 148)
3 (REF. 147)
Figure5.10 Representative structures of mono- and oligovalent PA-IL antagonists (1-5).
co-instillation of P. aeruginosa in a lung infection model in mice and therefore pro-
vides a promising drug candidate[149].
a
The proposed natural ligand of PA-IIL is the Lewis
trisaccharide, Galβ(1-3)
[Fucα(1-4)]GlcNAc, which shows a dissociation constant of 210 nM [137]. To
reduce the structural complexity of the trisaccharide, glycomimetics based on
either Fuc alone or the Fucα(1-4)GlcNAc disaccharide were designed and synthesized
(Figure5.11)[150–160].
The crystal structure of PA-IIL in complex with sulfonamide 6a (Figure5.11) provides insight into binding details. A hydrogen bond of the sulfonamide with the carboxylate of Asp96 and lipophilic contacts with the protein surface represent the most
1515.4 Pseudomonas aeruginosa Virulence Factors (PA-IL and PA-IIL)
0
Lewis
8 (REF. 156)
10 (REF. 158)
6a X = OMe, Y = H (REF. 153)
6b X = H, Y = Me (REF. 154)
9 (REF. 157)
7 (REF. 154)
11 (REF. 159)
12 (REF. 160)
Figure5.11 Representative structures of PA-IIL antagonists (6-11) and bifunctional
glycodendrimer (12).
5 Antiadhesive Carbohydrates and Glycomimetics
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152
important contacts in this glycomimetic/lectin interaction[153]. Further structural
optimization on the sulfonamide moiety resulted in two nanomolar glycomimetics
(6b and 7, Figure5.11) with excellent receptor-binding kinetics and thermodynamic
profiles[154]. Both 6b and 7 efficiently blocked biofilm formation of P. aeruginosa
in vitro and showed good oral bioavailability and pharmacokinetic properties
in vivo [155]. The α--fucoside 8 bearing an isoxazol sulfonamide (Figure 5.11)
a
showed a potency comparable to Lewis
a
, such as derivative 9 (Figure5.11) [157], also reached binding affinity in
Lewis
[156]. Additionally, partial structures of
nanomolar range. ITC experiment with 9 revealed that increased entropy costs upon
binding are probably related to increased flexibility of Fucα(1-4)GlcNAc compared to
a
, which, however, is overcompensated by an enthalpy gain resulting from an
Lewis
extended hydrogen network. Finally, oligovalent ligands bearing Fucα(1-4)GlcNAc
(→ 10, Figure5.11)[158] or -Fuc (→ 11, Figure5.11)[159] exhibit increased binding
activity toward PA-IIL; however, this effect is modest on a per saccharide basis.
Notably, heterobifunctional ligands presenting both -Gal and -Fuc in an oligovalent set-up (→ 12, Figure5.11)[160] showed efficacy in surgically stressed mice.
Whereas 60% of the control group died within 48 hours after acute infection with
P. aeruginosa, 100% of mice treated with 12 survived.
5.4.3 Conclusions and Perspectives
Studies on monovalent glycomimetics have revealed a series of high-affinity PA-IL
and PA-IIL antagonists with low toxicity, good metabolic stability, and oral bioavailability. A notable feature of some candidates is their inhibitory potency against biofilm formation without affecting bacterial viability. Therefore, development of
resistance toward these antibiofilm agents is unlikely, in contrast to traditional bactericidal or bacteriostatic antibiotics. Additionally, combining elements of both
PA-IL and PA-IIL antagonists in one molecule represents a new, therapeutically
valuable compound class for fighting P. aeruginosa infections. Future developments
could include evaluation of antiadhesive therapeutics in a monotherapy treatment
against biofilm-associated infections as well as their synergistic effects with antibiotics for eradication of bacteria outside biofilms[141, 142].
5.5 General Aspects
Two topics, namely resistance and affinity of carbohydrates, are of general importance and are therefore not presented in each chapter separately but in a general
form in this last chapter.
Resistance. Drug resistance reduces the effectiveness of a medication, such as an
antimicrobial or an antiviral, in treating a disease. The alarming increase in drugresistant bacteria makes a search for novel anti-infective drugs mandatory[161].
It is well established that adhesion of enteric, oral, and respiratory bacteria is
the initial step required for colonization and the subsequent development of
References
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monovalent interaction and gives thermodynamically complex systems with high
overall avidity. Inspired by nature, medicinal carbohydrate chemistry applies
comparable approaches to convert low-affinity natural carbohydrates or mediumaffinity glycomimetics into high-affinity, therapeutically valuable compounds.
153
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