Non-native autoinducer analogs capable of modulating the SdiA quorum sensing receptor in Salmonella enterica serovar Typhimurium

• Matthew J. Styles and
• Helen E. Blackwell

Beilstein J. Org. Chem. 2018, 14, 2651–2664, doi:10.3762/bjoc.14.243

• bacteriostatic chemotherapies to treat infection imposes evolutionary pressures that drive rapid resistance development and spread within and among bacterial populations [2][3]. Antibiotic resistant clinical isolates have been observed for almost every known antibiotic, and the pace of new antibiotic discovery

• has lagged behind [4]. In recent years, non-bacteriocidal approaches have emerged as a new therapeutic strategy to treat infection with potentially a lesser propensity for resistance development and spread [4][5][6]. Interfering with the regulation of virulence phenotypes represents one such approach

• ) operon; PefI negatively regulates the pef operon and SrgA is a disulfide oxidoreductase involved in correctly folding PefA, a fimbrial subunit [33]. The functions of SrgB-D are unknown [28]. SrgE is a type III secreted effector, but its target is unknown [19]. Lastly, rck (resistance to complement

The design and synthesis of an antibacterial phenothiazine–siderophore conjugate

• Abed Tarapdar,
• James K. S. Norris,
• Oliver Sampson,
• Galina Mukamolova and
• James T. Hodgkinson

Beilstein J. Org. Chem. 2018, 14, 2646–2650, doi:10.3762/bjoc.14.242

• antibacterial agents. Keywords: NDH-2; phenothiazine; siderophore; siderophore–antibiotic; siderophore conjugate; Introduction One of the biggest challenges facing the modern society is antibiotic resistance and the prospect of current antibiotics becoming near redundant against previously treatable

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

• recent years, attempts to raise public awareness on antimicrobial resistance (AMR) and the large threat that it poses towards modern health standards have been made [1]. It is an alarming notion that at an increasing rate of available treatment options proves ineffective in eradicating bacterial

• processes of the bacterial cell, ‘antivirulence’ strategies aim at abolishing pathogenic features without affecting cell viability, providing the basis for a lower drug-induced selection pressure [5][8][9]. Hence, a reduced rate of resistance development is expected [9]. A clinical proof-of-concept for this

• disruption of the Pseudomonas quinolone signal quorum sensing system (pqs QS). Review Antimicrobial resistance and clinical relevance of Pseudomonas aeruginosa P. aeruginosa is one of the threatening ESKAPE pathogens and has regularly been attributed with the label ‘superbug’ [11]. In 2017, the World Health

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

• -Braunschweig, Germany Department of Pharmacy, Saarland University, Saarbrücken, Germany 10.3762/bjoc.14.239 Abstract The rapid development of antimicrobial resistance is threatening mankind to such an extent that the World Health Organization expects more deaths from infections than from cancer in 2050 if

• for disarming pathogens. Furthermore, it is believed that this new approach is less susceptible towards resistance development. In this review, recent examples of anti-infective compounds acting on several types of bacterial targets, e.g., adhesins, toxins and bacterial communication, are described

• . Keywords: antimicrobial resistance; bacterial adhesins; bacterial toxins; pathoblockers; quorum sensing; Review 1. Antimicrobial resistance crisis for bacterial infections The current crisis caused by antimicrobial resistance [1][2] demands new strategies to fight infections. Antibiotics have served as

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

• 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

Comparative cell biological study of in vitro antitumor and antimetastatic activity on melanoma cells of GnRH-III-containing conjugates modified with short-chain fatty acids

• Eszter Lajkó,
• Sarah Spring,
• Rózsa Hegedüs,
• Beáta Biri-Kovács,
• Sven Ingebrandt,
• Gábor Mező and
• László Kőhidai

Beilstein J. Org. Chem. 2018, 14, 2495–2509, doi:10.3762/bjoc.14.226

• . Malignant melanoma, despite the improving chemotherapeutic and surgical strategies, remains the leading cause of skin cancer deaths. The strong ability to disseminate metastases and to develop resistance to chemotherapy results in poor prognosis especially in advanced cases [23]. The expression GnRH-R was

• anticancer drug resistance as they are co-administrated with other chemotherapeutics [29][30]. Nevertheless, there is some controversy about the effects of short-chain fatty acids on the metastatic ability of melanoma cells, since both pro-invasive [31] and anti-invasive [29][32] activities have been

• junctions, (ii) the seal resistance related to the cleft height between the cell and the electrode surface as well as (iii) the membrane capacitance correlated well with the amount of attached membrane area. The stronger adhesion could be due to a decrease in the cleft height, without any change in the

Synthesis of a leopolic acid-inspired tetramic acid with antimicrobial activity against multidrug-resistant bacteria

• Luce Mattio,
• Loana Musso,
• Leonardo Scaglioni,
• Andrea Pinto,
• Piera Anna Martino and
• Sabrina Dallavalle

Beilstein J. Org. Chem. 2018, 14, 2482–2487, doi:10.3762/bjoc.14.224

• , is an imperative goal to stay ahead of the evolution of antibiotic resistance. Herein we report the synthesis of a 3-decyltetramic acid analogue of the ureido dipeptide natural antibiotic leopolic acid A. The key step in the synthetic strategy is an intramolecular Lacey–Dieckmann cyclization reaction

• agar plates (Tryptic Soy Agar plus 5% defibrinated sheep blood, Microbiol, Italy) to obtain pure cultures [29]. The isolated colonies were used to assess the phenotypic profile of antimicrobial resistance. For this purpose, the Kirby Bauer disk diffusion method was used in accordance to Clinical

• strains, oxacillin was also tested to assess methicillin-resistance (see Table S1, Supporting Information File 1, for details). After incubation, 30 strains of S. pseudintermedius revealed resistance phenoptype to three or more pharmacological categories and were considered multidrug resistant (MDR) [31

Semi-synthesis and insecticidal activity of spinetoram J and its D-forosamine replacement analogues

• Kai Zhang,
• Jiarong Li,
• Honglin Liu,
• Haiyou Wang and
• Lamusi A

Beilstein J. Org. Chem. 2018, 14, 2321–2330, doi:10.3762/bjoc.14.207

• macrolide compounds, such as modification of the macrolide and the branched chain glycosyl residue, and replacement of the sugar group, are in the limelight [16][17]. The unique macrolide structure of spinosyns and the efficient appearance of resistance in some insect pests have prompted further exploration

Synthesis of new tricyclic 5,6-dihydro-4H-benzo[b][1,2,4]triazolo[1,5-d][1,4]diazepine derivatives by [3⁺ + 2]-cycloaddition/rearrangement reactions

• Lin-bo Luan,
• Zi-jie Song,
• Zhi-ming Li and
• Quan-rui Wang

Beilstein J. Org. Chem. 2018, 14, 1826–1833, doi:10.3762/bjoc.14.155

• examples of such clinically drugs having enhanced effects on the neurotransmitter γ-aminobutyric acid (GABA) at the GABAA receptor and low toxicity (Figure 1) [15]. Although 1,4-benzodiazepines are widely prescribed medicines, side effects like drowsiness, drug resistance, addiction and withdrawal

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

• (CSP), to acquire antibiotic resistance and establish an infection. In this work, we sought to define the binding pockets within the ComD1 receptor used for binding the hydrophobic side-chain residues in CSP1 through the introduction of highly-conservative point mutations within the peptide

• . Optimization of these binding interactions could lead to the development of highly potent CSP-based QS modulators while the inclusion of non-natural amino acids within the CSP sequence would confer resistance to protease degradation, a requirement for drug candidates. Keywords: binding surface; competence

• 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

Natural and redesigned wasp venom peptides with selective antitumoral activity

• Marcelo D. T. Torres,
• Gislaine P. Andrade,
• Roseli H. Sato,
• Cibele N. Pedron,
• Tania M. Manieri,
• Giselle Cerchiaro,
• Anderson O. Ribeiro,
• Cesar de la Fuente-Nunez and
• Vani X. Oliveira Jr.

Beilstein J. Org. Chem. 2018, 14, 1693–1703, doi:10.3762/bjoc.14.144

• conventional chemotherapy [11][12]. ACPs are promising anticancer compounds as they offer advantages such as higher specificity and lower incidence of acquired resistance in comparison to existing therapies [12][13][14]. ACPs derive from various sources and consequently share low homology [15][16][17][18

• -negative bacteria, fungi, and protozoa. However, both peptides presented high hemolytic activity, which limited their use as potential therapies. Torres et al. synthesized Dec-NH2 analogs with single and double substitutions, which exhibited increased resistance to degradation and lower hemolytic activity

Lanyamycin, a macrolide antibiotic from Sorangium cellulosum, strain Soce 481 (Myxobacteria)

• Lucky S. Mulwa,
• Rolf Jansen,
• Dimas F. Praditya,
• Kathrin I. Mohr,
• Patrick W. Okanya,
• Joachim Wink,
• Eike Steinmann and
• Marc Stadler

Beilstein J. Org. Chem. 2018, 14, 1554–1562, doi:10.3762/bjoc.14.132

• . Additionally, the treatment and management of viral and bacterial diseases is complicated by increasing rates of multidrug resistance. Hence, the need for new chemical scaffolds urgently required to increase the chemical diversity of drugs, especially to obtain antibiotics that overcome resistance by new modes

Cobalt–metalloid alloys for electrochemical oxidation of 5-hydroxymethylfurfural as an alternative anode reaction in lieu of oxygen evolution during water splitting

• Jonas Weidner,
• Stefan Barwe,
• Kirill Sliozberg,
• Stefan Piontek,
• Justus Masa,
• Ulf-Peter Apfel and
• Wolfgang Schuhmann

Beilstein J. Org. Chem. 2018, 14, 1436–1445, doi:10.3762/bjoc.14.121

• was determined by means of a pH electrode for high alkaline solutions (Dr. Kornder Anlagen- und Messtechnik, Germany) to be 14. RDE measurements were performed at a rotation speed of 1600 rpm. In order to correct the potential for the uncompensated electrolyte resistance, electrochemical impedance

• an EIS was recorded to determine the uncompensated electrolyte resistance and the potential was corrected accordingly. The conditioning of the catalyst was performed by cyclic voltammetry with 20 cycles between 0.97 V vs RHE and 1.43 V vs RHE with a scan rate of 100 mV s−1. The LSVs were measured

Spectroelectrochemical studies on the effect of cations in the alkaline glycerol oxidation reaction over carbon nanotube-supported Pd nanoparticles

• Dennis Hiltrop,
• Steffen Cychy,
• Karina Elumeeva,
• Wolfgang Schuhmann and
• Martin Muhler

Beilstein J. Org. Chem. 2018, 14, 1428–1435, doi:10.3762/bjoc.14.120

• ambient conditions. The catalyst-covered electrodes were initially conditioned in a potential range from 0.33 to 1.13 V vs RHE in Ar-saturated 1 M of alkali base + 1 M of glycerol for 10 cycles at a scan rate of 0.1 V s−1 and an electrode rotation rate of 1000 rpm. The uncompensated electrolyte resistance

One hundred years of benzotropone chemistry

• Arif Dastan,
• Haydar Kilic and
• Nurullah Saracoglu

Beilstein J. Org. Chem. 2018, 14, 1120–1180, doi:10.3762/bjoc.14.98

An overview of recent advances in duplex DNA recognition by small molecules

• Sayantan Bhaduri,
• Nihar Ranjan and
• Dev P. Arya

Beilstein J. Org. Chem. 2018, 14, 1051–1086, doi:10.3762/bjoc.14.93

• the inverted CCAAT box (ICB) of the human multidrug resistance 1 gene (MDR1) promoter and to distinguish between different promoter ICB sites, several ICB-containing DNA hairpin polyamides were designed with different flanking base pairs. It was confirmed via thermal-denaturation studies and DNase I

On the design principles of peptide–drug conjugates for targeted drug delivery to the malignant tumor site

• Eirinaios I. Vrettos,
• Gábor Mező and
• Andreas G. Tzakos

Beilstein J. Org. Chem. 2018, 14, 930–954, doi:10.3762/bjoc.14.80

• tissues, resulting in severe effects on the patient’s health. One representative example is gemcitabine, which demonstrates higher toxicity for healthy cells, after long-term administration, with respect to cancer cells. This happens since cancer cells evolve more rapidly and develop drug resistance by

• ], while the most frequently used GnRH analog is D-Lys6-GnRH-I, which is known to bind selectively to GnRH-R. The substitution of Gly6 of the native hormone with D-Lys6 provided an analog with higher binding affinity, stabilized β-bend and resistance to proteolytic cleavage. Moreover, the side chain of

• deactivation through deamination in its inactive metabolite dFdU, the acquired multidrug resistance (MDR) and its high hydrophilicity deterring its prolonged drug release from various vehicles [88], which therefore reduces the effective concentration of gemcitabine. It enters cells through nucleoside

Volatiles from three genome sequenced fungi from the genus Aspergillus

• Jeroen S. Dickschat,
• Ersin Celik and
• Nelson L. Brock

Beilstein J. Org. Chem. 2018, 14, 900–910, doi:10.3762/bjoc.14.77

• the penny bun (Boletus edulis) [7], but can also inhibit the growth of other fungi [8] which likely contributes to the induction of systemic resistance in plants by Trichoderma [9]. Fungal volatiles can also act as self-inhibitors of fungal germination [10] or as attractants for insects involved in

Volatiles from the xylarialean fungus Hypoxylon invadens

• Jeroen S. Dickschat,
• Tao Wang and
• Marc Stadler

Beilstein J. Org. Chem. 2018, 14, 734–746, doi:10.3762/bjoc.14.62

• (2), another widespread fungal volatile, a plant growth promoting effect and an induction of systemic resistance in plants against fungi was observed [5]. The significant biological effects of these and other fungal volatiles recently resulted in a considerable interest of natural product chemists

High-yielding continuous-flow synthesis of antimalarial drug hydroxychloroquine

• Eric Yu,
• Hari P. R. Mangunuru,
• Nakul S. Telang,
• Caleb J. Kong,
• Jenson Verghese,
• Stanley E. Gilliland III,
• Saeed Ahmad,
• Raymond N. Dominey and
• B. Frank Gupton

Beilstein J. Org. Chem. 2018, 14, 583–592, doi:10.3762/bjoc.14.45

• of the malaria parasite Plasmodium falciparum. Hydroxychloroquine (1) is an antimalarial drug developed for both treatment and prevention of the disease in response to the widespread malaria resistance to chloroquine (2, Figure 1) [5][6]. Additionally, hydroxychloroquine (1, HCQ) is an effective non

Stimuli-responsive oligonucleotides in prodrug-based approaches for gene silencing

• Françoise Debart,
• Christelle Dupouy and
• Jean-Jacques Vasseur

Beilstein J. Org. Chem. 2018, 14, 436–469, doi:10.3762/bjoc.14.32

• such as gene regulation is to circumvent the poor chemical stability of nucleic acids in biological media due to their low resistance to nucleases and to overcome their low cell uptake due to their polyanionic nature. In the present review, we aimed to identify various ON prodrugs that are responsive

• the modified ONs in addition to an increase in their nuclease resistance. Thus, two Japanese groups have proposed prodrug-type phosphotriester ONs responsive to GSH (Scheme 1) [13][14]. Ono presented a preliminary study on a model of a thymidine dimer with differently substituted benzyl groups at the

• ’-F, 2’-OMe) have been proposed to increase the nuclease resistance of ONs, but most of them have decreased gene silencing potential. To overcome this drawback, novel prodrug-type RNAs containing a disulfide bridge at the 2’-position have been designed, and in 2016, Urata and our group reported on the

Recent developments in the asymmetric Reformatsky-type reaction

• Hélène Pellissier

Beilstein J. Org. Chem. 2018, 14, 325–344, doi:10.3762/bjoc.14.21

• constituted the key step of a nine-step total synthesis of the eastern fragment of jatrophane diterpene Pl-3, which is a complex natural product with high promising biological activities, such as antiproliferative activity and inhibition of the efflux-pump activity of multidrug resistance P-glycoprotein. The

Volatiles from the tropical ascomycete Daldinia clavata (Hypoxylaceae, Xylariales)

• Tao Wang,
• Kathrin I. Mohr,
• Marc Stadler and
• Jeroen S. Dickschat

Beilstein J. Org. Chem. 2018, 14, 135–147, doi:10.3762/bjoc.14.9

• widespread fungal volatile is 6-pentyl-2H-pyran-2-one (2) that was first isolated from Trichoderma and exhibits a strong coconut aroma [5]. For fungi producing 2 a plant-growth promoting effect and an induction of systemic resistance in plants has been observed which makes these fungi interesting as

Aminosugar-based immunomodulator lipid A: synthetic approaches

• Alla Zamyatina

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

• 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

• ethanolamine that reduces the net negative charge and induces resistance to CAMPs (Figure 2). The unique structure of H. pylori lipid A plays a pivotal role in evading the host immune response by the bacterium [84]. Synthetically prepared structurally defined homogeneous H. pylori lipid A should help to

Position-dependent impact of hexafluoroleucine and trifluoroisoleucine on protease digestion

• Susanne Huhmann,
• Anne-Katrin Stegemann,
• Kristin Folmert,
• Damian Klemczak,
• Johann Moschner,
• Michelle Kube and
• Beate Koksch

Beilstein J. Org. Chem. 2017, 13, 2869–2882, doi:10.3762/bjoc.13.279

• proteolytic degradation in particular. Meng and Kumar reported that the incorporation of 5,5,5,5’,5’,5’-hexafluoroleucine (HfLeu) into the antimicrobial peptides magainin 2 amide and buforin enhanced their resistance towards proteolytic degradation by trypsin [23]. They also introduced HfLeu into the glucagon

• assay [30]. Substitution of tryptophan, tyrosine, and phenylalanine residues in a glycosylation-deficient mutant of Candida antarctica lipase B, CalB N74D, by their monofluorinated analogues, left the resistance to proteolytic degradation by proteinase K unchanged [31]. Incorporation of α-fluoroalkyl

• observed that the introduction of fluorine atoms into the Abu side chain can significantly improve or dramatically reduce resistance to hydrolysis by different enzymes and human blood plasma, depending upon the fluorine content of the side chain, the position of the substitution relative to the cleavage