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Design and Synthesis of Quorum-Sensing Inhibitors

A special issue of Molecules (ISSN 1420-3049). This special issue belongs to the section "Organic Chemistry".

Deadline for manuscript submissions: closed (15 October 2017) | Viewed by 19481

Special Issue Editor

Special Issue Information

Dear Colleagues,

With the long-term overuse and misuse of antibiotics, the problem of antibiotic-resistance is now reaching a critical stage. Antibiotics are no longer the magic bullets they were once thought to be and therefore there is an urgent need for development of alternative therapeutic strategies to combat infections without inducing drug resistance. Quorum-sensing (QS) inhibition presents a promising alternative strategy, since it attenuates bacterial virulence by disrupting the signaling pathway between bacteria without inducing stress.

Several strategies to combat this problem are discussed:

i)     Isolation of natural products with quorum sensing (QS) inhibitory activities and developing their synthetic analogues;
ii)    Synthesis of new classes of QSI with anti-virulence and anti-biofilm properties;
iii)   Rational design of QSIs;
iv)   Structure-activity relationship studies of QSIs;
v)    Applications and targeted delivery of QSIs;
vi)   Dual-action and hybrid QSIs;
vii)  Synergistic activities of QSIs.

Molecules will publish a Special Issue focusing on the “Design and Synthesis of Quorum-Sensing Inhibitors”, as well as novel molecular targets with reduced capacity to develop antibiotic resistance. It is my pleasure to invite submissions of high quality research-based papers related to the topics mentioned above.

Prof. Naresh Kumar
Guest Editor

Manuscript Submission Information

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Keywords

  • Discovery of new classes of quorum sensing inhibitors
  • Synthesis of quorum sensing inhibitors with antimicrobial activity
  • Rational design of quorum sensing inhibitors
  • Development of methods for the targeted delivery of quorum sensing inhibitors

Published Papers (3 papers)

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15 pages, 2813 KiB  
Article
Modification and Assembly of a Versatile Lactonase for Bacterial Quorum Quenching
by Melissa K. Rhoads, Pricila Hauk, Valerie Gupta, Michelle L. Bookstaver, Kristina Stephens, Gregory F. Payne and William E. Bentley
Molecules 2018, 23(2), 341; https://doi.org/10.3390/molecules23020341 - 06 Feb 2018
Cited by 7 | Viewed by 3987
Abstract
This work sets out to provide a self-assembled biopolymer capsule activated with a multi-functional enzyme for localized delivery. This enzyme, SsoPox, which is a lactonase and phosphotriesterase, provides a means of interrupting bacterial communication pathways that have been shown to mediate pathogenicity. [...] Read more.
This work sets out to provide a self-assembled biopolymer capsule activated with a multi-functional enzyme for localized delivery. This enzyme, SsoPox, which is a lactonase and phosphotriesterase, provides a means of interrupting bacterial communication pathways that have been shown to mediate pathogenicity. Here we demonstrate the capability to express, purify and attach SsoPox to the natural biopolymer chitosan, preserving its activity to “neutralize” long-chain autoinducer-1 (AI-1) communication molecules. Attachment is shown via non-specific binding and by engineering tyrosine and glutamine affinity ‘tags’ at the C-terminus for covalent linkage. Subsequent degradation of AI-1, in this case N-(3-oxododecanoyl)-l-homoserine lactone (OdDHL), serves to “quench” bacterial quorum sensing (QS), silencing intraspecies communication. By attaching enzymes to pH-responsive chitosan that, in turn, can be assembled into various forms, we demonstrate device-based flexibility for enzyme delivery. Specifically, we have assembled quorum-quenching capsules consisting of an alginate inner core and an enzyme “decorated” chitosan shell that are shown to preclude bacterial QS crosstalk, minimizing QS mediated behaviors. Full article
(This article belongs to the Special Issue Design and Synthesis of Quorum-Sensing Inhibitors)
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15 pages, 2224 KiB  
Article
In Silico and in Vitro-Guided Identification of Inhibitors of Alkylquinolone-Dependent Quorum Sensing in Pseudomonas aeruginosa
by Fadi Soukarieh, Eduard Vico Oton, Jean-Frédéric Dubern, Janice Gomes, Nigel Halliday, Maria De Pilar Crespo, Jonathan Ramírez-Prada, Braulio Insuasty, Rodrigo Abonia, Jairo Quiroga, Stephan Heeb, Paul Williams, Michael J. Stocks and Miguel Cámara
Molecules 2018, 23(2), 257; https://doi.org/10.3390/molecules23020257 - 28 Jan 2018
Cited by 46 | Viewed by 8276
Abstract
Pseudomonas aeruginosa is a major opportunistic pathogen in cystic fibrosis, wound and nosocomial infections, posing a serious burden to public health, due to its antibiotic resistance. The P. aeruginosa Pseudomonas Quinolone System (pqs) quorum sensing system, driven by the activation of [...] Read more.
Pseudomonas aeruginosa is a major opportunistic pathogen in cystic fibrosis, wound and nosocomial infections, posing a serious burden to public health, due to its antibiotic resistance. The P. aeruginosa Pseudomonas Quinolone System (pqs) quorum sensing system, driven by the activation of the transcriptional regulator, PqsR (MvfR) by alkylquinolone (AQ) signal molecules, is a key player in the regulation of virulence and a potential target for the development of novel antibacterial agents. In this study, we performed in silico docking analysis, coupled with screening using a P. aeruginosa mCTX::PpqsA-lux chromosomal promoter fusion, to identify a series of new PqsR antagonists. The hit compounds inhibited pyocyanin and alkylquinolone signal molecule production in P. aeruginosa PAO1-L and PA14 strains. The inhibitor Ia, which showed the highest activity in PA14, reduced biofilm formation in PAO1-L and PA14, increasing their sensitivity to tobramycin. Furthermore, the hepatic and plasma stabilities for these compounds were determined in both rat and human in vitro microsomal assays, to gain a further understanding of their therapeutic potential. This work has uncovered a new class of P. aeruginosa PqsR antagonists with potential for hit to lead optimisation in the search for quorum sensing inhibitors for future anti-infective drug discovery programs. Full article
(This article belongs to the Special Issue Design and Synthesis of Quorum-Sensing Inhibitors)
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2950 KiB  
Article
2-Substituted Aniline as a Simple Scaffold for LuxR-Regulated QS Modulation
by Sizhe Li, Julien Wawrzyniak, Yves Queneau and Laurent Soulère
Molecules 2017, 22(12), 2090; https://doi.org/10.3390/molecules22122090 - 29 Nov 2017
Cited by 5 | Viewed by 6398
Abstract
The ability of the 2-substituted aniline motif to serve as a scaffold for designing potential LuxR-regulated quorum sensing (QS) modulators has been investigated, using docking experiments and biological evaluation of a series of 15 specially synthesized compounds. Aniline, 2-acetyl-aniline and 2-nitroaniline were considered, [...] Read more.
The ability of the 2-substituted aniline motif to serve as a scaffold for designing potential LuxR-regulated quorum sensing (QS) modulators has been investigated, using docking experiments and biological evaluation of a series of 15 specially synthesized compounds. Aniline, 2-acetyl-aniline and 2-nitroaniline were considered, as well as their N-acylated derivatives. Docking experiments showed that the 2-substituted aniline motif fits within the LuxR binding site at the place of the lactone moiety of AHL, and the biological evaluation revealed QS antagonisitic activity for several compounds, validating the hypothesis that this scaffold acts on QS. Structure activity relationships are discussed regarding interactions with the key residues of the LuxR binding site, showing significant variations in the H-bonding pattern. Full article
(This article belongs to the Special Issue Design and Synthesis of Quorum-Sensing Inhibitors)
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