Targeting the Pseudomonas quinolone signal quorum sensing system for the discovery of novel anti-infective pathoblockers

• Christian Schütz and
• Martin Empting

Beilstein J. Org. Chem. 2018, 14, 2627–2645, doi:10.3762/bjoc.14.241

• coordinate population-wide group behaviours in the infection process like concerted secretion of virulence factors. One very important signalling network is the Pseudomonas quinolone signal (PQS) QS. With the aim to devise novel and innovative anti-infectives, inhibitors have been designed to address the

• bactericidal or bacteriostatic effects, but mediate their effect through pathogen-specific action on virulence mechanisms, has been unveiled. This short review focuses on the current knowledge of one particular antivirulence strategy against the important pathogen Pseudomonas aeruginosa, which is based on the

• pathogenicity traits like the production of virulence factors or biofilm formation are under the control of these systems. Actually, title pathogen makes use of four intertwined QS systems, referred to as las, rhl, pqs, and iqs [22]. These subsystems influence each other establishing an intricate regulatory

Pathoblockers or antivirulence drugs as a new option for the treatment of bacterial infections

• Matthew B. Calvert,
• Varsha R. Jumde and
• Alexander Titz

Beilstein J. Org. Chem. 2018, 14, 2607–2617, doi:10.3762/bjoc.14.239

• current trends continue. To avoid this scenario, new classes of anti-infectives must urgently be developed. Antibiotics with new modes of action are needed, but other concepts are also currently being pursued. Targeting bacterial virulence as a means of blocking pathogenicity is a promising new strategy

• treatments are urgently needed. 2. Concept of antivirulence drugs or pathoblockers Bacterial virulence is the prime determinant for the deterioration of an infected patient’s health. Blocking bacterial virulence, or pathogenicity, is a new approach that has emerged over the last decade [7][8][9]. The

• pioneering review by Clatworthy et al. in 2007, entitled ‘Targeting virulence: a new paradigm for antimicrobial therapy’ [8], which has been cited approximately 800 times. In sharp contrast to traditional antibiotics that kill or impair bacterial viability, this new approach aims to disarm the pathogen

Impact of Pseudomonas aeruginosa quorum sensing signaling molecules on adhesion and inflammatory markers in endothelial cells

• Carmen Curutiu,
• Florin Iordache,
• Veronica Lazar,
• Aurelia Magdalena Pisoschi,
• Aneta Pop,
• Mariana Carmen Chifiriuc and
• Alina Maria Hoban

Beilstein J. Org. Chem. 2018, 14, 2580–2588, doi:10.3762/bjoc.14.235

• central regulator mechanism of virulence expression that contributes to the formation and maintenance of biofilms and tolerance to conventional antimicrobials. QS Signaling molecules (QSSMs) may be recognized and may function also within the host cells, being potentially involved in the progression of the

• compromised individuals and in patients with bronchiectasis or cystic fibrosis. The infections become chronic, as P. aeruginosa develops resistance to conventional antibiotics due to its ability to produce virulence factors and modulate immune defenses by quorum sensing (QS) and biofilm production

• infection, inflammation and respiratory insufficiency [2]. P. aeruginosa pathogenesis is multifactorial, as suggested by the large number and wide spectrum of bacterial virulence factors present either attached to the cell wall or extracellular virulence factors capable of producing massive tissue damage

Diazirine-functionalized mannosides for photoaffinity labeling: trouble with FimH

• Femke Beiroth,
• Tomas Koudelka,
• Thorsten Overath,
• Stefan D. Knight,
• Andreas Tholey and
• Thisbe K. Lindhorst

Beilstein J. Org. Chem. 2018, 14, 1890–1900, doi:10.3762/bjoc.14.163

• ) of bacteria to the glycosylated surface of their target cells and constitute important virulence factors in bacterial infection such as urinary tract infection [13][14][15][16]. Hence, FimH is an interesting target protein in medicinal chemistry and proteomics [17][18]. It is a two-domain protein

Defining the hydrophobic interactions that drive competence stimulating peptide (CSP)-ComD binding in Streptococcus pneumoniae

• Bimal Koirala,
• Robert A. Hillman,
• Erin K. Tiwold,
• Michael A. Bertucci and
• Yftah Tal-Gan

Beilstein J. Org. Chem. 2018, 14, 1769–1777, doi:10.3762/bjoc.14.151

• , swarming, biofilm formation, virulence factor production and competence [3][4][5]. As such, QS has attracted significant attention as a means to control bacterial behaviors (i.e., promote productive processes while attenuating harmful traits). Extensive work aimed at developing small molecule-based QS

• as the competence regulon, is centered on the competence stimulating peptide (CSP, Figure 1). S. pneumoniae utilizes the regulon to become competent and acquire antibiotic resistance from the environment, initiate its attack on the human host through virulence factor production, and protect itself

• threshold concentration, CSP binds and activates the transmembrane histidine kinase receptor ComD. Upon activation, ComD phosphorylates ComE. Phosphorylated ComE then autoactivates the competence QS circuit and upregulates the expression of genes involved in virulence factor production, biofilm formation

Aminosugar-based immunomodulator lipid A: synthetic approaches

• Alla Zamyatina

Beilstein J. Org. Chem. 2018, 14, 25–53, doi:10.3762/bjoc.14.3

• mammalian immune cells such as macrophages, monocytes and dendritic cells [4]. LPS represents the major virulence factor of Gram-negative bacteria and is essential for bacterial survival. LPS constitutes the outer leaflet of the outer membrane of Gram-negative bacteria (Figure 1A) and possesses a complex

• to the phosphate groups of lipid A alters the TLR4-mediated host immunity and accounts for the modulation of the pro-inflammatory signaling. Additionally, this modification is associated with an amplified bacterial virulence since it confers resistance to the endogenous cationic antimicrobial

The chemistry and biology of mycolactones

• Matthias Gehringer and
• Karl-Heinz Altmann

Beilstein J. Org. Chem. 2017, 13, 1596–1660, doi:10.3762/bjoc.13.159

• ulcerans, which exhibit cytotoxic, immunosuppressive and analgesic properties. As the virulence factor of M. ulcerans, mycolactones are central to the pathogenesis of the neglected disease Buruli ulcer, a chronic and debilitating medical condition characterized by necrotic skin ulcers. Due to their complex

• virulence factor [32][33]. The initial characterization of the toxin relied on the separation of extract components by thin layer chromatography (TLC) and the biological characterization of the individual bands, a process that revealed a light yellow UV-active component to possess the highest cytopathogenic

• origin and its chemical structure, this compound was named mycolactone. It is worth noting that mycolactone represented the first polyketide macrolide isolated from a mycobacterial species and was also the first example of a polyketide acting as the virulence factor of a human pathogen [34]. The purified

Chemical probes for competitive profiling of the quorum sensing signal synthase PqsD of Pseudomonas aeruginosa

• Michaela Prothiwa,
• Dávid Szamosvári,
• Sandra Glasmacher and
• Thomas Böttcher

Beilstein J. Org. Chem. 2016, 12, 2784–2792, doi:10.3762/bjoc.12.277

• coordinate the production of its broad spectrum of virulence factors to facilitate colonization and infection of its host. Hereby, the enzyme PqsD is a virulence related quorum sensing signal synthase that catalyzes the central step in the biosynthesis of the Pseudomonas quinolone signals HHQ and PQS. We

• fibrosis patients [2][3]. P. aeruginosa deploys numerous virulence factors such as toxins, extracellular enzymes, and small molecule factors that are responsible for the bacterium’s ability to invade the host and cause a broad spectrum of different diseases [4][5]. The production of these virulence factors

• is coordinated on population level by several layers of hierarchically interconnected quorum sensing systems [6]. Quorum sensing signals are released from the cells and accumulate in a growing bacterial population to a certain threshold by which they start inducing the production of virulence factors

Automated glycan assembly of a S. pneumoniae serotype 3 CPS antigen

• Markus W. Weishaupt,
• Stefan Matthies,
• Mattan Hurevich,
• Claney L. Pereira,
• Heung Sik Hahm and
• Peter H. Seeberger

Beilstein J. Org. Chem. 2016, 12, 1440–1446, doi:10.3762/bjoc.12.139

• finally elucidated in 1941 [11], as being composed of repeating units of β-(1,3)-linked cellobiuronic acid (Figure 1). CPS plays a major role in S. pneumoniae virulence [12]. A commercial 17-valent polysaccharide vaccine was introduced in 1977, followed by a 23-valent vaccine in 1983 [13][14][15

Discovery of an inhibitor of the production of the Pseudomonas aeruginosa virulence factor pyocyanin in wild-type cells

• Bernardas Morkunas,
• Balint Gal,
• Warren R. J. D. Galloway,
• James T. Hodgkinson,
• Brett M. Ibbeson,
• Yaw Sing Tan,
• Martin Welch and
• David R. Spring

Beilstein J. Org. Chem. 2016, 12, 1428–1433, doi:10.3762/bjoc.12.137

• combat P. aeruginosa infections [1][2][3][4][5][6][7][8][9][10][11][12]. P. aeruginosa can secrete small organic molecules, exoenzymes, tissue degrading enzymes, toxins and other substrates which damage physiological functions of the host causing disease, often termed ‘virulence factors’ [13][14][15][16

• ]. Pyocyanin is an important redox active small molecule virulence factor which is widely considered to play a crucial role in the pathogenesis of P. aeruginosa infections (Figure 1) [8][9][17][18]. The inhibition of pyocyanin production has been identified as an attractive antivirulence strategy for the

• pyocyanin biosynthesis in P. aeruginosa may be inhibitors of LasR-based quorum sensing. However, it has previously been reported that P. aeruginosa can exhibit near full virulence, including pyocyanin production, in the absence of LasR utilising solely the rhl, and pqs signalling systems [30]. Additional

Natural products from microbes associated with insects

• Christine Beemelmanns,
• Huijuan Guo,
• Maja Rischer and
• Michael Poulsen

Beilstein J. Org. Chem. 2016, 12, 314–327, doi:10.3762/bjoc.12.34

• evolutionary-based refinement for at least a billion years [9][10][11]. They function as chemical modulators and signaling molecules for intra- and interkingdom interactions such as defense, protection, behavior, virulence, and central physiological functions; thereby generating evolutionary benefits for the

• occurrence of these metabolites in often subinhibitory concentrations indicates that they might not primarily function as antimicrobials. Rather they work as signaling molecules leading to modulation of gene expression in the target organism, to alteration in factors contributing to the virulence or

• for bioactive secondary metabolites. The respective natural products are predicted to play key roles as chemical signals or virulence factors mediating the interactions with the respective insect host [108][109][110][111]. Despite the fact that a few examples exist, fungi as (defensive) symbionts have

Synthesis and biological evaluation of novel N-α-haloacylated homoserine lactones as quorum sensing modulators

• Michail Syrpas,
• Ewout Ruysbergh,
• Christian V. Stevens,
• Norbert De Kimpe and
• Sven Mangelinckx

Beilstein J. Org. Chem. 2014, 10, 2539–2549, doi:10.3762/bjoc.10.265

• target genes important for phenotype expression (e.g., biofilm formation, bioluminescence, virulence expression, etc.) in a population density dependent manner [2]. The importance of QS for virulence development in pathogenic bacteria nowadays is obvious [3]. Therefore, quorum sensing modulation is seen

• as a new anti-infective strategy [4]. Although the described QS systems can regulate virulence, it is believed that they do not affect the viability of bacteria and it could be expected that disruption of QS will not likely create a selective pressure towards resistant organisms [5]. Despite recent

Expeditive synthesis of trithiotriazine-cored glycoclusters and inhibition of Pseudomonas aeruginosa biofilm formation

• Meriem Smadhi,
• Sophie de Bentzmann,
• Anne Imberty,
• Marc Gingras,
• Raoudha Abderrahim and
• Peter G. Goekjian

Beilstein J. Org. Chem. 2014, 10, 1981–1990, doi:10.3762/bjoc.10.206

• ) is an opportunistic human pathogen known to cause a variety of hospital-borne infections. It poses a severe threat to immunocompromised patients, as well as to those suffering from cystic fibrosis or cancer [1][2][3]. Its virulence is largely associated with multi-resistance to antibiotics, in

• particular due to the physical barrier created by surface-attached biofilms, thus limiting antibiotic penetration [4][5][6]. A challenging and useful task is therefore to develop novel strategies against PA colonies at this late stage of virulence. Among recent approaches, targeting biofilm formation or

• target for pharmacological intervention. Further investigations of the specific functions played by these lectins in PA biofilm formation will provide useful understanding, and ultimately a means of prevention of PA virulence. The creative design of glycomimetics that can interfere or can modulate the

Convergent synthetic methodology for the construction of self-adjuvanting lipopeptide vaccines using a novel carbohydrate scaffold

• Vincent Fagan,
• Istvan Toth and
• Pavla Simerska

Beilstein J. Org. Chem. 2014, 10, 1741–1748, doi:10.3762/bjoc.10.181

• B cell epitopes used was the J8-peptide antigen. This epitope was identified from the conserved C-terminal region of the M protein (a cell surface protein and a major virulence factor) of S. pyogenes [19]. For comparison purposes, the J8 epitope was also employed in the current studies. The

Carbohydrate PEGylation, an approach to improve pharmacological potency

• M. Eugenia Giorgi,
• Rosalía Agusti and
• Rosa M. de Lederkremer

Beilstein J. Org. Chem. 2014, 10, 1433–1444, doi:10.3762/bjoc.10.147

• trans-sialidase (TcTS) [48], a virulence factor of Trypanosoma cruzi [49][50][51]. It was shown that lactitol prevented apoptosis caused by TcTS although it is rapidly eliminated from the circulatory system [52]. With the aim to improve bioavailability, PEGylation of lactose analogs was performed using

Straightforward synthesis of a tetrasaccharide repeating unit corresponding to the O-antigen of Escherichia coli O16

• Manas Jana and
• Anup Kumar Misra

Beilstein J. Org. Chem. 2013, 9, 1757–1762, doi:10.3762/bjoc.9.203

• virulence property of the pathogen, several reports appeared in the past on the development of glycoconjugate based therapeutics against bacterial infections [10][11][12]. Detailed biological studies of the glycoconjugates require a significant quantity of the oligosaccharides, which is difficult to isolate

De novo synthesis of D- and L-fucosamine containing disaccharides

• Daniele Leonori and
• Peter H. Seeberger

Beilstein J. Org. Chem. 2013, 9, 332–341, doi:10.3762/bjoc.9.38

• bacteria Pseudomonas aeruginosa. P. aeruginosa is a nosocomial pathogen that is involved in ventilator-associated pneumonia and has become resistant to many antimicrobials. The somatic pili of P. aeruginosa are a major virulence factor playing a pivotal role in the adherence and invasiveness of the

Efficient synthesis of phenylene-ethynylene rods and their use as rigid spacers in divalent inhibitors

• Francesca Pertici,
• Norbert Varga,
• Arnoud van Duijn,
• Matias Rey-Carrizo,
• Anna Bernardi and
• Roland J. Pieters

Beilstein J. Org. Chem. 2013, 9, 215–222, doi:10.3762/bjoc.9.25

• of aromatic rings. One of the spacers was incorporated into the structure of a divalent galactoside ligand and was used to inhibit the virulence-linked lectin LecA of Pseudomonas aeruginosa [27][28]. Results and Discussion Synthetic strategies Depending on the number of units in the spacer, two

• obtained after deprotection of the alkyne moieties with K2CO3. Preliminary application As part of our program on bacterial adhesion inhibition by multivalent carbohydrates, the bacterial lectin LecA, a virulence factor of the problematic pathogen Pseudomonas aeruginosa is a target of interest [30][31

Convergent synthesis of the tetrasaccharide repeating unit of the cell wall lipopolysaccharide of Escherichia coli O40

• Abhijit Sau and
• Anup Kumar Misra

Beilstein J. Org. Chem. 2012, 8, 2053–2059, doi:10.3762/bjoc.8.230

• can kill harmful bacteria by producing vitamins and other immunostimulants [3]. However, a number of E. coli strains acquire virulence factors and cause severe intestinal and urinary-tract infections [4][5]. E. coli serotypes are generally classified based on the somatic, flagella and capsular

Volatile organic compounds produced by the phytopathogenic bacterium Xanthomonas campestris pv. vesicatoria 85-10

• Teresa Weise,
• Marco Kai,
• Anja Gummesson,
• Armin Troeger,
• Stephan von Reuß,
• Silvia Piepenborn,
• Francine Kosterka,
• Martin Sklorz,
• Ralf Zimmermann,
• Wittko Francke and
• Birgit Piechulla

Beilstein J. Org. Chem. 2012, 8, 579–596, doi:10.3762/bjoc.8.65

• by Xanthomonas species include diseases such as bacterial spot on peppers and tomatoes, citrus canker, and bacterial blight disease in rice [9][10]. Unravelling the mechanisms for phytopathogenicity and virulence of X. campestris resulted in the identification of a type-three secretion system through

Mutational analysis of a phenazine biosynthetic gene cluster in Streptomyces anulatus 9663

• Orwah Saleh,
• Katrin Flinspach,
• Lucia Westrich,
• Andreas Kulik,
• Bertolt Gust,
• Hans-Peter Fiedler and
• Lutz Heide

Beilstein J. Org. Chem. 2012, 8, 501–513, doi:10.3762/bjoc.8.57

• antiparasitic activities, and as inhibitors of angiotensin converting enzyme (ACE) or testosterone-5-α-reductase [1]. The synthetic phenazine clofazimine has been approved for human therapy in the treatment of leprosy. Some of the other naturally occurring phenazines are bacterial virulence factors [1]. Natural

Facile synthesis of nitrophenyl 2-acetamido-2-deoxy-α-D-mannopyranosides from ManNAc-oxazoline

• Karel Křenek,
• Petr Šimon,
• Lenka Weignerová,
• Barbora Fliedrová,
• Marek Kuzma and
• Vladimír Křen

Beilstein J. Org. Chem. 2012, 8, 428–432, doi:10.3762/bjoc.8.48

• partly to the content of ManNAc. Thus, ManNAc units play a significant role in bacterial pathogenicity and virulence (e.g., Streptococcus pneumoniae) [4][5]. Surprisingly, glycosidases active upon β-ManpNAc and α-ManpNAc glycosides are not known so far. Therefore, the building blocks for the chemical

One-pot three-component synthesis of quinoxaline and phenazine ring systems using Fischer carbene complexes

• Priyabrata Roy and
• Binay Krishna Ghorai

Beilstein J. Org. Chem. 2010, 6, No. 52, doi:10.3762/bjoc.6.52

• heterocycles which exhibit a wide range of biological activities. Many phenazine compounds are found in nature and are produced by bacteria such as Pseudomonas spp., Streptomyces spp. and Pantoea agglomerans. These phenazine natural products have been implicated in the virulence and competitive fitness of the