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      Design and Synthesis of Lactams Derived from Mucochloric and Mucobromic Acids as Pseudomonas aeruginosa Quorum Sensing Inhibitors

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          Abstract

          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.

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          Exploiting quorum sensing to confuse bacterial pathogens.

          Cell-cell communication, or quorum sensing, is a widespread phenomenon in bacteria that is used to coordinate gene expression among local populations. Its use by bacterial pathogens to regulate genes that promote invasion, defense, and spread has been particularly well documented. With the ongoing emergence of antibiotic-resistant pathogens, there is a current need for development of alternative therapeutic strategies. An antivirulence approach by which quorum sensing is impeded has caught on as a viable means to manipulate bacterial processes, especially pathogenic traits that are harmful to human and animal health and agricultural productivity. The identification and development of chemical compounds and enzymes that facilitate quorum-sensing inhibition (QSI) by targeting signaling molecules, signal biogenesis, or signal detection are reviewed here. Overall, the evidence suggests that QSI therapy may be efficacious against some, but not necessarily all, bacterial pathogens, and several failures and ongoing concerns that may steer future studies in productive directions are discussed. Nevertheless, various QSI successes have rightfully perpetuated excitement surrounding new potential therapies, and this review highlights promising QSI leads in disrupting pathogenesis in both plants and animals.
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            Regulation of gene expression by cell-to-cell communication: acyl-homoserine lactone quorum sensing.

            Quorum sensing is an example of community behavior prevalent among diverse bacterial species. The term "quorum sensing" describes the ability of a microorganism to perceive and respond to microbial population density, usually relying on the production and subsequent response to diffusible signal molecules. A significant number of gram-negative bacteria produce acylated homoserine lactones (acyl-HSLs) as signal molecules that function in quorum sensing. Bacteria that produce acyl-HSLs can respond to the local concentration of the signaling molecules, and high population densities foster the accumulation of inducing levels of acyl-HSLs. Depending upon the bacterial species, the physiological processes regulated by quorum sensing are extremely diverse, ranging from bioluminescence to swarming motility. Acyl-HSL quorum sensing has become a paradigm for intercellular signaling mechanisms. A flurry of research over the past decade has led to significant understanding of many aspects of quorum sensing including the synthesis of acyl-HSLs, the receptors that recognize the acyl-HSL signal and transduce this information to the level of gene expression, and the interaction of these receptors with the transcriptional machinery. Recent studies have begun to integrate acyl-HSL quorum sensing into global regulatory networks and establish its role in developing and maintaining the structure of bacterial communities.
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              Listening in on bacteria: acyl-homoserine lactone signalling.

              Bacterial cell-to-cell signalling has emerged as a new area in microbiology. Individual bacterial cells communicate with each other and co-ordinate group activities. Although a lot of detail is known about the mechanisms of a few well-characterized bacterial communication systems, other systems have been discovered only recently. Bacterial intercellular communication has become a target for the development of new anti-virulence drugs.
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                Author and article information

                Journal
                Molecules
                Molecules
                molecules
                Molecules : A Journal of Synthetic Chemistry and Natural Product Chemistry
                MDPI
                1420-3049
                07 May 2018
                May 2018
                : 23
                : 5
                : 1106
                Affiliations
                [1 ]School of Chemistry, UNSW Australia, Sydney, NSW 2052, Australia; b.almohaywi@ 123456unsw.edu.au (B.A.); a.taunk@ 123456unsw.edu.au (A.T.); d.wenholz@ 123456unsw.edu.au (D.S.W.); s.nizalapur@ 123456unsw.edu.au (S.N.); nnathbiswas@ 123456gmail.com (N.N.B.); kitty.ho@ 123456unsw.edu.au (K.K.K.H.); g.iskander@ 123456unsw.edu.au (G.I.); d.black@ 123456unsw.edu.au (D.S.B.)
                [2 ]School of Pharmacy, King Khalid University, Abha 62529, Saudi Arabia
                [3 ]The Singapore Centre of Environmental Life Sciences Engineering, Nanyang Technological University, Singapore 639798, Singapore; RSCOTT@ 123456ntu.edu.sg
                [4 ]School of Medical Science, UNSW Australia, Sydney, NSW 2052, Australia; r.griffith@ 123456unsw.edu.edu.au
                Author notes
                [* ]Correspondence: n.kumar@ 123456unsw.edu.au ; Tel.: +61-29385-4698; Fax: +61-29385-6141
                Author information
                https://orcid.org/0000-0001-8504-0375
                https://orcid.org/0000-0003-2830-3938
                Article
                molecules-23-01106
                10.3390/molecules23051106
                6100351
                29735954
                547f8f36-ae93-40c1-9f8b-6d228ab4ae16
                © 2018 by the authors.

                Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license ( http://creativecommons.org/licenses/by/4.0/).

                History
                : 18 April 2018
                : 05 May 2018
                Categories
                Article

                quorum sensing,pseudomonas aeruginosa,lactam,mucochloric acid,mucobromic acid

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