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Interactions of Bacterial Molecules with Their Ligands and Other Chemical Agents

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Special Issue Information
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A special issue of Molecules (ISSN 1420-3049). This special issue belongs to the section "Bioorganic Chemistry".

Deadline for manuscript submissions: closed (20 November 2021) | Viewed by 13042

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Special Issue Editor

Dr. Mary K. Phillips-Jones

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Guest Editor

National Centre for Macromolecular Hydrodynamics (NCMH) (Limes Building), School of Biosciences, Sutton Bonington Campus, Sutton Bonington, Leicestershire LE12 5RD, UK
Interests: bacterial signal transduction; two-component signal transduction systems; bacterial gene regulation; antibiotic sensing; antimicrobial resistance; vancomycin modes of action; glycopeptide resistance

Special Issue Information

Dear Colleagues,

The World Health Organization warns that infectious diseases due to microorganisms kill over 17 million people per year and that we face a global crisis in an era of increasing microbial resistance to current therapies. Bacteria constitute a significant proportion of the microbial threat, as we see the return of cholera, malaria and tuberculosis in many parts of the world and an increasing prevalence of other bacterial diseases such as sepsis and pneumonia. The need to find new therapies has hardly ever been greater.

This Special Issue of Molecules welcomes original research articles and reviews that address molecular interactions between bacterial components and their ligands and with other chemical entities. Studies concerning such interactions that show potential or early-stage promise for the future development of new antibiotics that inhibit or interfere with novel (and well-established) bacterial targets are especially welcome. This includes studies that could potentially lead to strategies for overcoming antibacterial resistance mechanisms.

Approximately twenty years ago, the genome sequences of hundreds of bacteria became available, and promising bacterial targets were identified at that time for the development of novel and new antibiotics; we also welcome articles that evaluate the outcomes of, and report progress from, those earlier identified bacterial target–ligand interaction studies.

Dr. Mary K. Phillips-Jones
Guest Editor

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. Molecules is an international peer-reviewed open access semimonthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 2700 CHF (Swiss Francs). Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

Bacteria–ligand interactions
Bacteria–ligand interactions in antibacterial resistance
Targets for potential drug development
Chemical inhibitors
Interference with bacteria–ligand interactions
Future and potential drug development

Published Papers (4 papers)

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Research

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19 pages, 2664 KiB

Open AccessArticle

Membrane Transporters Involved in the Antimicrobial Activities of Pyrithione in Escherichia coli

by Jesus Enrique Salcedo-Sora, Amy T. R. Robison, Jacqueline Zaengle-Barone, Katherine J. Franz and Douglas B. Kell

Molecules 2021, 26(19), 5826; https://doi.org/10.3390/molecules26195826 - 26 Sep 2021

Cited by 7 | Viewed by 2512

Abstract

Pyrithione (2-mercaptopyridine-N-oxide) is a metal binding modified pyridine, the antibacterial activity of which was described over 60 years ago. The formulation of zinc-pyrithione is commonly used in the topical treatment of certain dermatological conditions. However, the characterisation of the cellular uptake of pyrithione has not been elucidated, although an unsubstantiated assumption has persisted that pyrithione and/or its metal complexes undergo a passive diffusion through cell membranes. Here, we have profiled specific membrane transporters from an unbiased interrogation of 532 E. coli strains of knockouts of genes encoding membrane proteins from the Keio collection. Two membrane transporters, FepC and MetQ, seemed involved in the uptake of pyrithione and its cognate metal complexes with copper, iron, and zinc. Additionally, the phenotypes displayed by CopA and ZntA knockouts suggested that these two metal effluxers drive the extrusion from the bacterial cell of potentially toxic levels of copper, and perhaps zinc, which hyperaccumulate as a function of pyrithione. The involvement of these distinct membrane transporters contributes to the understanding of the mechanisms of action of pyrithione specifically and highlights, more generally, the important role that membrane transporters play in facilitating the uptake of drugs, including metal–drug compounds. Full article

(This article belongs to the Special Issue Interactions of Bacterial Molecules with Their Ligands and Other Chemical Agents)

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15 pages, 13470 KiB

Open AccessArticle

An Investigation into the Potential of Targeting Escherichia coli rne mRNA with Locked Nucleic Acid (LNA) Gapmers as an Antibacterial Strategy

by Layla R. Goddard, Charlotte E. Mardle, Hassan Gneid, Ciara G. Ball, Darren M. Gowers, Helen S. Atkins, Louise E. Butt, Jonathan K. Watts, Helen A. Vincent and Anastasia J. Callaghan

Molecules 2021, 26(11), 3414; https://doi.org/10.3390/molecules26113414 - 4 Jun 2021

Viewed by 3002

Abstract

The increase in antibacterial resistance is a serious challenge for both the health and defence sectors and there is a need for both novel antibacterial targets and antibacterial strategies. RNA degradation and ribonucleases, such as the essential endoribonuclease RNase E, encoded by the rne gene, are emerging as potential antibacterial targets while antisense oligonucleotides may provide alternative antibacterial strategies. As rne mRNA has not been previously targeted using an antisense approach, we decided to explore using antisense oligonucleotides to target the translation initiation region of the Escherichia coli rne mRNA. Antisense oligonucleotides were rationally designed and were synthesised as locked nucleic acid (LNA) gapmers to enable inhibition of rne mRNA translation through two mechanisms. Either LNA gapmer binding could sterically block translation and/or LNA gapmer binding could facilitate RNase H-mediated cleavage of the rne mRNA. This may prove to be an advantage over the majority of previous antibacterial antisense oligonucleotide approaches which used oligonucleotide chemistries that restrict the mode-of-action of the antisense oligonucleotide to steric blocking of translation. Using an electrophoretic mobility shift assay, we demonstrate that the LNA gapmers bind to the translation initiation region of E. coli rne mRNA. We then use a cell-free transcription translation reporter assay to show that this binding is capable of inhibiting translation. Finally, in an in vitro RNase H cleavage assay, the LNA gapmers facilitate RNase H-mediated mRNA cleavage. Although the challenges of antisense oligonucleotide delivery remain to be addressed, overall, this work lays the foundations for the development of a novel antibacterial strategy targeting rne mRNA with antisense oligonucleotides. Full article

(This article belongs to the Special Issue Interactions of Bacterial Molecules with Their Ligands and Other Chemical Agents)

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14 pages, 2914 KiB

Open AccessArticle

Identification of Novel Inhibitors of Escherichia coli DNA Ligase (LigA)

by Arqam Alomari, Robert Gowland, Callum Southwood, Jak Barrow, Zoe Bentley, Jashel Calvin-Nelson, Alice Kaminski, Matthew LeFevre, Anastasia J. Callaghan, Helen A. Vincent and Darren M. Gowers

Molecules 2021, 26(9), 2508; https://doi.org/10.3390/molecules26092508 - 25 Apr 2021

Cited by 2 | Viewed by 3045

Abstract

Present in all organisms, DNA ligases catalyse the formation of a phosphodiester bond between a 3′ hydroxyl and a 5′ phosphate, a reaction that is essential for maintaining genome integrity during replication and repair. Eubacterial DNA ligases use NAD⁺ as a cofactor and possess low sequence and structural homology relative to eukaryotic DNA ligases which use ATP as a cofactor. These key differences enable specific targeting of bacterial DNA ligases as an antibacterial strategy. In this study, four small molecule accessible sites within functionally important regions of Escherichia coli ligase (EC-LigA) were identified using in silico methods. Molecular docking was then used to screen for small molecules predicted to bind to these sites. Eight candidate inhibitors were then screened for inhibitory activity in an in vitro ligase assay. Five of these (geneticin, chlorhexidine, glutathione (reduced), imidazolidinyl urea and 2-(aminomethyl)imidazole) showed dose-dependent inhibition of EC-LigA with half maximal inhibitory concentrations (IC₅₀) in the micromolar to millimolar range (11–2600 µM). Two (geneticin and chlorhexidine) were predicted to bind to a region of EC-LigA that has not been directly investigated previously, raising the possibility that there may be amino acids within this region that are important for EC-LigA activity or that the function of essential residues proximal to this region are impacted by inhibitor interactions with this region. We anticipate that the identified small molecule binding sites and inhibitors could be pursued as part of an antibacterial strategy targeting bacterial DNA ligases. Full article

(This article belongs to the Special Issue Interactions of Bacterial Molecules with Their Ligands and Other Chemical Agents)

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Review

Jump to: Research

25 pages, 2982 KiB

Open AccessReview

Membrane Sensor Histidine Kinases: Insights from Structural, Ligand and Inhibitor Studies of Full-Length Proteins and Signalling Domains for Antibiotic Discovery

by Pikyee Ma and Mary K. Phillips-Jones

Molecules 2021, 26(16), 5110; https://doi.org/10.3390/molecules26165110 - 23 Aug 2021

Cited by 10 | Viewed by 3879

Abstract

There is an urgent need to find new antibacterial agents to combat bacterial infections, including agents that inhibit novel, hitherto unexploited targets in bacterial cells. Amongst novel targets are two-component signal transduction systems (TCSs) which are the main mechanism by which bacteria sense and respond to environmental changes. TCSs typically comprise a membrane-embedded sensory protein (the sensor histidine kinase, SHK) and a partner response regulator protein. Amongst promising targets within SHKs are those involved in environmental signal detection (useful for targeting specific SHKs) and the common themes of signal transmission across the membrane and propagation to catalytic domains (for targeting multiple SHKs). However, the nature of environmental signals for the vast majority of SHKs is still lacking, and there is a paucity of structural information based on full-length membrane-bound SHKs with and without ligand. Reasons for this lack of knowledge lie in the technical challenges associated with investigations of these relatively hydrophobic membrane proteins and the inherent flexibility of these multidomain proteins that reduces the chances of successful crystallisation for structural determination by X-ray crystallography. However, in recent years there has been an explosion of information published on (a) methodology for producing active forms of full-length detergent-, liposome- and nanodisc-solubilised membrane SHKs and their use in structural studies and identification of signalling ligands and inhibitors; and (b) mechanisms of signal sensing and transduction across the membrane obtained using sensory and transmembrane domains in isolation, which reveal some commonalities as well as unique features. Here we review the most recent advances in these areas and highlight those of potential use in future strategies for antibiotic discovery. This Review is part of a Special Issue entitled “Interactions of Bacterial Molecules with Their Ligands and Other Chemical Agents” edited by Mary K. Phillips-Jones. Full article

(This article belongs to the Special Issue Interactions of Bacterial Molecules with Their Ligands and Other Chemical Agents)

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