The Quorum-sensing system in Pseudomonas aeruginosa is responsible for the pathogenicity and the production of virulence factors and biofilm formation. Dihydropyrrolones were previously found to act as inhibitors of QS-dependent bacterial phenotypes. In this study, a range of dihydropyrrolone (DHP) analogues was synthesized via the lactone-lactam conversion of lactone intermediates followed by the formation of novel acetylene analogues of dihydropyrrolones from brominated dihydropyrrolones via Sonogashira coupling reactions in moderate to high yields. Upon biological testing, the most potent compounds, 39–40 and 44, showed higher bacterial quorum-sensing inhibitory (QSI) activity against P. aeruginosa reporter strain at 62.5 µM. Structure–activity relationship studies revealed that di-alkynyl substituent at the exocyclic position of DHPs possessed higher QSI activities than those of mono-alkynyl DHPs. Moreover, a hexyl-substituent at C3 of DHPs was beneficial to QSI activity while a phenyl substituent at C4 of DHPs was detrimental to QSI activity of analogues.

The quorum sensing (QS) system in multi-drug-resistant bacteria such as P. aeruginosa is primarily responsible for the development of antibiotic resistance and is considered an attractive target for antimicrobial drug discovery. In this study, we synthesised a series of novel selenourea and thiourea-containing dihydropyrrol-2-one (DHP) analogues as LasR antagonists. The selenium DHP derivatives displayed significantly better quorum-sensing inhibition (QSI) activities than the corresponding sulphur analogues. The most potent analogue 3e efficiently inhibited the las QS system by 81% at 125 µM and 53% at 31 µM. Additionally, all the compounds were screened for their minimum inhibitory concentration (MIC) against the Gram-positive bacterium S. aureus, and interestingly, only the selenium analogues showed antibacterial activity, with 3c and 3e being the most potent with a MIC of 15.6 µM.

Quorum sensing (QS) signaling system is important for bacterial growth, adhesion, and biofilm formation resulting in numerous infectious diseases. Dihydropyrrol-2-ones (DHPs) represent a novel class of antimicrobial agents that inhibit QS, and are less prone to develop bacterial resistance due to their non-growth inhibition mechanism of action which does not cause survival pressure on bacteria. DHPs can prevent bacterial colonization and quorum sensing when covalently bound to substrates. In this study, the role of orientation of DHP compounds was investigated after covalent attachment by 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (EDC)/N-hydroxysuccinimide (NHS) coupling reaction to amine-functionalized glass surfaces via various positions of the DHP scaffold. The functionalized glass surfaces were characterized by X-ray photoelectron spectroscopy (XPS) and contact angle measurements and tested for their in vitro biological activity against S. aureus and P. aeruginosa. DHPs attached via the N-1 position resulted in the highest antibacterial activities against S. aureus, while no difference was observed for DHPs attached either via the N-1 position or the C-4 phenyl ring against P. aeruginosa.

Bacteria regulate their pathogenicity and biofilm formation through quorum sensing (QS), which is an intercellular communication system mediated by the binding of signaling molecules to QS receptors such as LasR. In this study, a range of dihydropyrrolone (DHP) analogues were synthesized via the lactone-lactam conversion of lactone intermediates. The synthesized compounds were tested for their ability to inhibit QS, biofilm formation and bacterial growth of Pseudomonas aeruginosa. The compounds were also docked into a LasR crystal structure to rationalize the observed structure-activity relationships. The most active compound identified in this study was compound 9i, which showed 63.1% QS inhibition of at 31.25 µM and 60% biofilm reduction at 250 µM with only moderate toxicity towards bacterial cell growth.

Bacterial biofilms on implanted medical devices are a serious problem. At present, no effective strategies are available and the emergence of multidrug resistance has highlighted the need to develop novel antibacterial coatings to combat device-related infections. One approach is to interfere with the bacterial communication pathway or quorum sensing (QS), which is responsible for biofilm formation and virulence factors, by incorporating QS inhibitors (QSIs) such as dihydropyrrolones (DHPs) on biomaterial surfaces. The endogenous biological signaling molecule nitric oxide (NO) is also a potential candidate for prevention of biomedical infections due to its antibiofilm activity. In this study, we have developed dual-action surface coatings based on DHPs and NO. X-ray photoelectron spectroscopy (XPS) and contact angle measurements confirmed successful immobilization of DHPs and NO, and the Griess assay revealed NO release from the coatings at 24 h. Bacterial colonization on the surfaces was assessed by confocal laser scanning microscopy (CLSM), where the DHP+NO surfaces demonstrated significantly higher efficacy in reducing colonization of Staphylococcus aureus and Pseudomonas aeruginosa via a nonbactericidal mechanism than the DHP or NO-releasing coatings alone. The excellent antibacterial activity of the novel coatings suggests the combination of DHP and NO has great potential to combat device-related bacterial infections.

Gram-negative bacteria such as Pseudomonas aeruginosa use furanosyl diesters as autoinducers for quorum sensing (QS), a major regulatory and cell-to-cell communication system for social adaptation, virulence factor production, biofilm formation, and antibiotic resistance. A range of natural and synthetic brominated furanones, i.e. fimbrolide derivatives, have been found to act as inhibitors of QS-dependent bacterial phenotypes, complementing the bactericidal ability of traditional antibiotics. In this work, several novel acetylene analogues of fimbrolides were synthesised in moderate to high yields via Sonogashira coupling reactions of brominated furanones 4-bromo-5-(bromomethylene)furan-2(5H)-one 4 and 5-(dibromomethylene)-3-ethylfuran-2(5H)-one 5. The Sonogashira reaction of acetylenes on 4-bromo-5-(bromomethylene) furan-2(5H)-one 4 was favoured at the C5 methylene bromide over the C4 bromide substituent. On biological testing, the most potent compounds 13 and 14 showed 82 and 98% bacterial quorum-sensing inhibitory (QSI) activity against Pseudomonas aeruginosa reporter strain respectively.

Bacterial infections, particularly hospital-acquired infections caused by Pseudomonas aeruginosa, have become a global threat with a high mortality rate. Gram-negative bacteria including P. aeruginosa employ N-acyl homoserine lactones (AHLs) as chemical signals to regulate the expression of pathogenic phenotypes through a mechanism called quorum sensing (QS). Recently, strategies targeting bacterial behaviour or QS have received great attention due to their ability to disarm rather than kill pathogenic bacteria, which lowers the evolutionary burden on bacteria and the risk of resistance development. In the present study, we report the design and synthesis of N-alkyl- and N-aryl 3,4 dichloro- and 3,4-dibromopyrrole-2-one derivatives through the reductive amination of mucochloric and mucobromic acid with aliphatic and aromatic amines. The quorum sensing inhibition (QSI) activity of the synthesized compounds was determined against a P. aeruginosa MH602 reporter strain. The phenolic compounds exhibited the best activity with 80% and 75% QSI at 250 µM and were comparable in activity to the positive control compound Fu-30. Computational docking studies performed using the LasR receptor protein of P. aeruginosa suggested the importance of hydrogen bonding and hydrophobic interactions for QSI.

A simple and efficient procedure for the synthesis of N-aryl 5-methylene-4-aryl-1,5-dihydro-2H-pyrrol2-one derivatives has been developed through copper-mediated C-N bond formation. The synthetic protocol allows for versatile and robust C-N arylation with a range of readily available boronic acids under mild conditions. (C) 2018 Elsevier Ltd. All rights reserved.

Infection of implanted medical devices is one of the major causes of nosocomial infections. A significant proportion of the devices become colonized by bacterial biofilms, thus resulting in high morbidity and risk of mortality. This study focuses on the non-specific covalent attachment of potent quorum sensing (QS) and biofilm inhibiting compounds, furanones (FUs) and dihydropyrrol-2-ones (DHPs), onto glass surfaces by azide/nitrene chemistry. The attachment of FUs and DHPs was confirmed by X-ray photoelectron spectroscopy (XPS) and contact angle measurements. The modified surfaces were then assessed for their antibacterial efficacy against Staphylococcus aureus and Pseudomonas aeruginosa using confocal laser scanning microscopy (CLSM). Both FU and DHP coated surfaces were able to significantly reduce bacterial adhesion (p<0.001) with p-bromophenyl substituted DHP giving maximum reductions of up to 93% and 71% against S. aureus and P. aeruginosa, respectively. Therefore, photoimmobilization of QS inhibitors is an effective technique to produce novel antibacterial biomaterial surfaces.

In this article, a number of novel brominated heterocycles based on aminobromopyrrolone, bromopyridazinone and hydrazinyl furanone scaffolds were synthesized from the reactions of brominated furanones with bi-nucleophiles, such as substituted or unsubstituted hydrazines. Some of these compounds were found to be effective quorum sensing (QS) inhibitors against Pseudomonas aeruginosa.

An entry from the Cambridge Structural Database, the world’s repository for small molecule crystal structures. The entry contains experimental data from a crystal diffraction study. The deposited dataset for this entry is freely available from the CCDC and typically includes 3D coordinates, cell parameters, space group, experimental conditions and quality measures.

Event Abstract Back to Event Immobilization of quorum sensing inhibitors to develop antibacterial biomaterials Aditi Taunk1, George Iskander1, Kitty Ka Kit Ho1, Mark D. Willcox2 and Naresh Kumar1 1 University of New South Wales, School of Chemistry, Australia 2 University of New South Wales, School of Optometry and Vision Science, Australia Introduction: The use of life-saving biomaterial implants and medical devices has increased tremendously over the past few years. One major complication with the long term use of biomaterials is bacterial biofilm formation. About 60-70% of hospital-acquired infections are due to implanted medical devices[1]. Treatment or removal of these infected devices is often troublesome for the patient resulting in high rates of morbidity and mortality as well as high medical cost[2],[3]. Also, rapid development of antibacterial resistance and lack of efficient strategies that can reduce the incidence of bacterial infections have made this a challenging problem to overcome. Therefore, in order to prevent infections associated with medical devices, coatings that interfere with the bacterial communication pathways known as quorum sensing (QS) instead of killing the bacteria have been developed. Materials and Methods: In this study, potent quorum sensing inhibitors (QSI) including halogenated furanones (FUs) and dihydropyrrolones (DHPs) were immobilized on surfaces. The FUs were attached via a non-specific nitrene insertion method [Fig 1], and DHPs with free carboxylic acid group were synthesized and attached covalently on amine functionalized surface via EDC/NHS coupling reaction [Fig 2]. The covalent attachment of DHPs was characterized by X-ray photoelectron spectroscopy (XPS) and contact angle measurement. Antibacterial activity of the DHP surfaces was assessed against two common pathogens, Staphylococcus aureus and Pseudomonas aeruginosa, using confocal laser scanning microscopy (CLSM). Results and Discussion: The XPS and contact angle measurements confirmed the successful attachment of brominated FUs via the nitrene insertion reaction and DHPs via EDC/NHS reaction. XPS detection of 0.17-0.74% Br from FUs and 0.17% F and 0.3% Br from 4-fluorophenyl and 4-bromophenyl DHP confirmed the efficacy of the coating strategy. All FU and DHP coated surfaces were able to significantly reduce the formation of biofilm against both S. aureus and P. aeruginosa. The activity of the coating was dependent upon the type of substituent present on the phenyl group of the DHP compound. For example, the ortho-fluorophenyl DHP (DHP-2) exhibited 79% reduction in bacterial adhesion against S. aureus and para-fluorophenyl DHP (DHP-3) exhibited 70% reduction against P. aeruginosa. The results were found to be comparable to other DHP coatings developed in previous studies. Conclusion: The furanone and DHP immobilised surfaces show high levels of inhibition of bacterial biofilm formation and may represent an effective strategy to develop new antibacterial coatings. UNSW Analytical Center for XPS, NMR data; UNSW Biomedical Imaging Facility for confocal microscopy; Australian government for the Australian Postgraduate Award (APA) scholarshipReferences:[1] Bryers, J. D. Medical biofilms. Biotechnol. Bioeng.100, 1–18 (2008).[2] Cruickshank, M. & Ferguson, J. Reducing harm to patients from health care associated infection : the role of surveillance. (2008)[3] Australian Guidlines for the prevention and control of infection in healthcare-executive summary. Aust. Goverment - Natl. Heal. Med. Res. Counc. (2010). Keywords: Bacteria, Infection, biomaterial, Surface modification Conference: 10th World Biomaterials Congress, Montréal, Canada, 17 May - 22 May, 2016. Presentation Type: Poster Topic: Anti-infective biomaterials Citation: Taunk A, Iskander G, Ho K, Willcox MD and Kumar N (2016). Immobilization of quorum sensing inhibitors to develop antibacterial biomaterials. Front. Bioeng. Biotechnol. Conference Abstract: 10th World Biomaterials Congress. doi: 10.3389/conf.FBIOE.2016.01.02320 Copyright: The abstracts in this collection have not been subject to any Frontiers peer review or checks, and are not endorsed by Frontiers. They are made available through the Frontiers publishing platform as a service to conference organizers and presenters. The copyright in the individual abstracts is owned by the author of each abstract or his/her employer unless otherwise stated. Each abstract, as well as the collection of abstracts, are published under a Creative Commons CC-BY 4.0 (attribution) licence (https://creativecommons.org/licenses/by/4.0/) and may thus be reproduced, translated, adapted and be the subject of derivative works provided the authors and Frontiers are attributed. For Frontiers’ terms and conditions please see https://www.frontiersin.org/legal/terms-and-conditions. Received: 27 Mar 2016; Published Online: 30 Mar 2016. Login Required This action requires you to be registered with Frontiers and logged in. To register or login click here. Abstract Info Abstract The Authors in Frontiers Aditi Taunk George Iskander Kitty Ka Kit Ho Mark D Willcox Naresh Kumar Google Aditi Taunk George Iskander Kitty Ka Kit Ho Mark D Willcox Naresh Kumar Google Scholar Aditi Taunk George Iskander Kitty Ka Kit Ho Mark D Willcox Naresh Kumar PubMed Aditi Taunk George Iskander Kitty Ka Kit Ho Mark D Willcox Naresh Kumar Related Article in Frontiers Google Scholar PubMed Abstract Close Back to top Javascript is disabled. Please enable Javascript in your browser settings in order to see all the content on this page.

Pseudomonas aeruginosa is an opportunistic pathogen causing a variety of life-threatening diseases such as cystic fibrosis and nosocomial infections in burn victims. The ability of P. aeruginosa to cause infection is attributed to the production of virulence factors such as pyocyanin and elastases. These virulence factors are under the control of quorum sensing (QS) a cell to cell communication process controlled by small diffusible signalling molecules based on N-acyl-homoserine lactones (AHLs) known as autoinducers. The inhibition of QS and thereby virulence factors is seen as a potential new anti-infective strategy. Additionally, the role of nitric oxide (NO) in downstream processes in bacteria such as biofilm dispersal, motility, virulence and antimicrobial defence systems is gaining attention and could be used to control bacterial. Herein we report the design and synthesis of hybrid compounds based on AHL signalling molecules and NO donors as anti-infective agents. A series of AHL-NO hybrids were synthesised and potent inhibitors of QS and virulence factors of P. aeruginosa were identified. This research has led to conversion of agonist AHLs to antagonist AHLs with dual properties of QS inhibition and NO release.

An entry from the Cambridge Structural Database, the world’s repository for small molecule crystal structures. The entry contains experimental data from a crystal diffraction study. The deposited dataset for this entry is freely available from the CCDC and typically includes 3D coordinates, cell parameters, space group, experimental conditions and quality measures.

Selenosemicarbazones show marked antitumor activity. However, their mechanism of action remains unknown. We examined the medicinal chemistry of the selenosemicarbazone, 2-acetylpyridine 4,4-dimethyl-3-selenosemicarbazone (Ap44mSe), and its iron and copper complexes to elucidate its mechanisms of action. Ap44mSe demonstrated a pronounced improvement in selectivity toward neoplastic relative to normal cells compared to its parent thiosemicarbazone. It also effectively depleted cellular Fe, resulting in transferrin receptor-1 up-regulation, ferritin down-regulation, and increased expression of the potent metastasis suppressor, N-myc downstream regulated gene-1. Significantly, Ap44mSe limited deleterious methemoglobin formation, highlighting its usefulness in overcoming toxicities of clinically relevant thiosemicarbazones. Furthermore, Cu-Ap44mSe mediated intracellular reactive oxygen species generation, which was attenuated by the antioxidant, N-acetyl-L-cysteine, or Cu sequestration. Notably, Ap44mSe forms redox active Cu complexes that target the lysosome to induce lysosomal membrane permeabilization. This investigation highlights novel structure-activity relationships for future chemotherapeutic design and underlines the potential of Ap44mSe as a selective anticancer/antimetastatic agent.

A one-step procedure for the synthesis of 4-amidoisoflavans from isoflavanols is described. The synthetic protocol allows for the introduction of a variety of substituents to the isoflavan scaffold via an amide linker.

Gram-negative bacteria such as Pseudomonas aeruginosa use N-acylated L-homoserine lactones (AHLs) as autoinducers (AIs) for quorum sensing (QS), a major regulatory and cell-to-cell communication system for social adaptation, virulence factor production, biofilm formation and antibiotic resistance. Some bacteria use indole moieties for intercellular signaling and as regulators of various bacterial phenotypes important for evading the innate host immune response and antimicrobial resistance. A range of natural and synthetic indole derivatives have been found to act as inhibitors of QS-dependent bacterial phenotypes, complementing the bactericidal ability of traditional antibiotics. In this work, various indole-based AHL mimics were designed and synthesized via the 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (EDC·HCl) and N,N'-dicyclohexylcarbodiimide (DCC) mediated coupling reactions of a variety of substituted or unsubstituted aminoindoles with different alkanoic acids. All synthesized compounds were tested for QS inhibition using a P. aeruginosa QS reporter strain by measuring the amount of green fluorescent protein (GFP) production. Docking studies were performed to examine their potential to bind and therefore inhibit the target QS receptor protein. The most potent compounds 11a, 11d and 16a showed 44 to 65% inhibition of QS activity at 250 μM concentration, and represent promising drug leads for the further development of anti-QS antimicrobial compounds.

Several novel functionalised thiophenes have been synthesised via an unusual acid catalysed reaction of S-acetyl fimbrolides. The crystal structure analysis of one of the thiophene products reveals interesting intermolecular hydrogen bonding and carbonyl–carbonyl (CO⋯CO) dipolar interactions.

Isoflavene-propranolol hybrid molecules were developed as potentially novel anti-tumour agents. Isoflavene itself has potent anti-cancer activity while propranolol can enhance anti-proliferative and anti-angiogenic properties of 5-fluorouracil and paclitaxel. The hybrids were produced via nucleophilic addition of substituted amine groups to a dioxiran intermediate, which was in turn generated from the Williamson-type reaction of isoflavene with (±)-epichlorohydrin. These analogues were tested in anti-cancer cell viability assays against SHEP neuroblastoma and MDA-MB-231 breast adenocarcinoma cell lines, and were found to exhibit potent anti-proliferative activities. These compounds also displayed anti-angiogenic and anti-proliferative effects in HMEC-1 human microvascular endothelial cell lines. Notably, the most potent hybrid molecules synthesized in this work showed enhanced potency against cancer cell lines compared to either isoflavene or propranolol alone, while retaining significant selectivity for cancer cells over MRC-5 normal lung fibroblast cells.