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Antibiotics
Special Issues
Antibiotic Targets in Bacterial DNA Replication and Cell Division
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Antibiotic Targets in Bacterial DNA Replication and Cell Division

A special issue of Antibiotics (ISSN 2079-6382).

Deadline for manuscript submissions: closed (31 August 2020) | Viewed by 26832

Special Issue Editors

Prof. Dr. Anders Løbner-Olesen

E-Mail Website
Guest Editor
Department of Biology, University of Copenhagen, 2200 Copenhagen, Denmark
Interests: bacterial cell cycle; mechanism and regulation of chromosomal replication initiation; initiator proteins; DNA methylation; antibiotic inhibition of chromosome replication; designing whole cell screens for discovery of new antibiotics; antimicrobial peptides
Special Issues, Collections and Topics in MDPI journals
Prof. Dr. Nicholas Dixon

E-Mail Website
Guest Editor
School of Chemistry and Molecular Bioscience, University of Wollongong, Wollongong, NSW 2522, Australia
Interests: bacterial DNA replication; protein-protein interactions; protein-DNA interactions; enzymes; antibiotic drug discovery
Special Issues, Collections and Topics in MDPI journals
Prof. Dr. Elizabeth Harry

E-Mail Website
Guest Editor
The ithree institute, University of Technology Sydney (UTS), P.O. Box 123, Broadway, NSW 2007, Australia
Interests: bacterial cell division; medicinal honey; natural product antibacterials; mechanisms of action of antibiotics; drug discovery (including natural products, antibiotic resistance)

Special Issue Information

Dear Colleagues,

This issue of Antibiotics is dedicated to the topics of Bacterial DNA Replication and Cell Division and Inhibitors of these processes. DNA replication is a conserved and essential process in all organisms, yet significant differences exist between replication proteins of bacteria and eukaryotic cells. Following replication initiation, for most bacteria governed by the DnaA protein, replication of the bacterial chromosome is carried out by a multi-protein complex called the replisome, which is present in only few copies per cell. The proteins involved in DNA replication should provide an attractive target for antimicrobial inhibition and yet only antibiotics that indirectly target the replication process are in clinical use. These inhibit the type-II topoisomerases that relieve topological stress created by DNA unwinding and decatenate daughter chromosomes prior to cell division.

The process of cell division is also an essential process, elements of which are widely conserved in bacteria. Like DNA replication, bacterial cell division involves a multiprotein assembly, called the divisome, and the process occurs quite differently from division of eukaryotic cells. Discovery of inhibitors of bacterial cell division have focussed on the conserved FtsZ protein that oligomerizes to form contractile rings at the site of division and the enzymes required for peptidoglycan synthesis, but there are many other potential targets.

This Special Issue summarizes current knowledge of bacterial DNA replication and cell division, and their inhibition by antimicrobials. It is our pleasure to invite submissions of high quality primary research manuscripts and review articles addressing the molecular mechanisms of bacterial DNA replication and cell division, their coordination and regulation, and their inhibition by established drugs and novel compounds.

Prof. Dr. Anders Løbner-Olesen
Prof. Dr. Nicholas Dixon
Prof. Dr. Elizabeth Harry
Guest Editors

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. Antibiotics is an international peer-reviewed open access monthly 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 2900 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

  • bacterial chromosomes
  • chromosome and plasmid replication
  • bacterial cell division
  • replication control
  • control of cell division
  • replication enzymes
  • cell division proteins
  • initiation, elongation and termination of replication
  • replisome, function and processivity
  • divisome, structure and function
  • protein-protein interactions
  • inhibition
  • antimicrobials
  • antibiotic resistance

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Published Papers (5 papers)

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Research

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22 pages, 6403 KiB  
Article
Benzamide Derivatives Targeting the Cell Division Protein FtsZ: Modifications of the Linker and the Benzodioxane Scaffold and Their Effects on Antimicrobial Activity
by Valentina Straniero, Lorenzo Suigo, Andrea Casiraghi, Victor Sebastián-Pérez, Martina Hrast, Carlo Zanotto, Irena Zdovc, Carlo De Giuli Morghen, Antonia Radaelli and Ermanno Valoti
Antibiotics 2020, 9(4), 160; https://doi.org/10.3390/antibiotics9040160 - 4 Apr 2020
Cited by 19 | Viewed by 4368
Abstract
Filamentous temperature-sensitive Z (FtsZ) is a prokaryotic protein with an essential role in the bacterial cell division process. It is widely conserved and expressed in both Gram-positive and Gram-negative strains. In the last decade, several research groups have pointed out molecules able to [...] Read more.
Filamentous temperature-sensitive Z (FtsZ) is a prokaryotic protein with an essential role in the bacterial cell division process. It is widely conserved and expressed in both Gram-positive and Gram-negative strains. In the last decade, several research groups have pointed out molecules able to target FtsZ in Staphylococcus aureus, Bacillus subtilis and other Gram-positive strains, with sub-micromolar Minimum Inhibitory Concentrations (MICs). Conversely, no promising derivatives active on Gram-negatives have been found up to now. Here, we report our results on a class of benzamide compounds, which showed comparable inhibitory activities on both S. aureus and Escherichia coli FtsZ, even though they proved to be substrates of E. coli efflux pump AcrAB, thus affecting the antimicrobial activity. These surprising results confirmed how a single molecule can target both species while maintaining potent antimicrobial activity. A further computational study helped us decipher the structural features necessary for broad spectrum activity and assess the drug-like profile and the on-target activity of this family of compounds. Full article
(This article belongs to the Special Issue Antibiotic Targets in Bacterial DNA Replication and Cell Division)
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Review

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14 pages, 15277 KiB  
Review
Novel Antibiotics Targeting Bacterial Replicative DNA Polymerases
by Joana A. Santos and Meindert H. Lamers
Antibiotics 2020, 9(11), 776; https://doi.org/10.3390/antibiotics9110776 - 4 Nov 2020
Cited by 18 | Viewed by 6225
Abstract
Multidrug resistance is a worldwide problem that is an increasing threat to global health. Therefore, the development of new antibiotics that inhibit novel targets is of great urgency. Some of the most successful antibiotics inhibit RNA transcription, RNA translation, and DNA replication. Transcription [...] Read more.
Multidrug resistance is a worldwide problem that is an increasing threat to global health. Therefore, the development of new antibiotics that inhibit novel targets is of great urgency. Some of the most successful antibiotics inhibit RNA transcription, RNA translation, and DNA replication. Transcription and translation are inhibited by directly targeting the RNA polymerase or ribosome, respectively. DNA replication, in contrast, is inhibited indirectly through targeting of DNA gyrases, and there are currently no antibiotics that inhibit DNA replication by directly targeting the replisome. This contrasts with antiviral therapies where the viral replicases are extensively targeted. In the last two decades there has been a steady increase in the number of compounds that target the bacterial replisome. In particular a variety of inhibitors of the bacterial replicative polymerases PolC and DnaE have been described, with one of the DNA polymerase inhibitors entering clinical trials for the first time. In this review we will discuss past and current work on inhibition of DNA replication, and the potential of bacterial DNA polymerase inhibitors in particular as attractive targets for a new generation of antibiotics. Full article
(This article belongs to the Special Issue Antibiotic Targets in Bacterial DNA Replication and Cell Division)
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28 pages, 2616 KiB  
Review
Targeting Bacterial Cell Division: A Binding Site-Centered Approach to the Most Promising Inhibitors of the Essential Protein FtsZ
by Andrea Casiraghi, Lorenzo Suigo, Ermanno Valoti and Valentina Straniero
Antibiotics 2020, 9(2), 69; https://doi.org/10.3390/antibiotics9020069 - 7 Feb 2020
Cited by 46 | Viewed by 6757
Abstract
Binary fission is the most common mode of bacterial cell division and is mediated by a multiprotein complex denominated the divisome. The constriction of the Z-ring splits the mother bacterial cell into two daughter cells of the same size. The Z-ring is formed [...] Read more.
Binary fission is the most common mode of bacterial cell division and is mediated by a multiprotein complex denominated the divisome. The constriction of the Z-ring splits the mother bacterial cell into two daughter cells of the same size. The Z-ring is formed by the polymerization of FtsZ, a bacterial protein homologue of eukaryotic tubulin, and it represents the first step of bacterial cytokinesis. The high grade of conservation of FtsZ in most prokaryotic organisms and its relevance in orchestrating the whole division system make this protein a fascinating target in antibiotic research. Indeed, FtsZ inhibition results in the complete blockage of the division system and, consequently, in a bacteriostatic or a bactericidal effect. Since many papers and reviews already discussed the physiology of FtsZ and its auxiliary proteins, as well as the molecular mechanisms in which they are involved, here, we focus on the discussion of the most compelling FtsZ inhibitors, classified by their main protein binding sites and following a medicinal chemistry approach. Full article
(This article belongs to the Special Issue Antibiotic Targets in Bacterial DNA Replication and Cell Division)
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17 pages, 861 KiB  
Review
Blocking the Trigger: Inhibition of the Initiation of Bacterial Chromosome Replication as an Antimicrobial Strategy
by Julia E. Grimwade and Alan C. Leonard
Antibiotics 2019, 8(3), 111; https://doi.org/10.3390/antibiotics8030111 - 6 Aug 2019
Cited by 10 | Viewed by 4840
Abstract
All bacterial cells must duplicate their genomes prior to dividing into two identical daughter cells. Chromosome replication is triggered when a nucleoprotein complex, termed the orisome, assembles, unwinds the duplex DNA, and recruits the proteins required to establish new replication forks. Obviously, the [...] Read more.
All bacterial cells must duplicate their genomes prior to dividing into two identical daughter cells. Chromosome replication is triggered when a nucleoprotein complex, termed the orisome, assembles, unwinds the duplex DNA, and recruits the proteins required to establish new replication forks. Obviously, the initiation of chromosome replication is essential to bacterial reproduction, but this process is not inhibited by any of the currently-used antimicrobial agents. Given the urgent need for new antibiotics to combat drug-resistant bacteria, it is logical to evaluate whether or not unexploited bacterial processes, such as orisome assembly, should be more closely examined for sources of novel drug targets. This review will summarize current knowledge about the proteins required for bacterial chromosome initiation, as well as how orisomes assemble and are regulated. Based upon this information, we discuss current efforts and potential strategies and challenges for inhibiting this initiation pharmacologically. Full article
(This article belongs to the Special Issue Antibiotic Targets in Bacterial DNA Replication and Cell Division)
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Other

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5 pages, 775 KiB  
Commentary
Counting Replication Origins to Measure Growth of Pathogens
by Godefroid Charbon, Maria Schei Haugan, Niels Frimodt-Møller and Anders Løbner-Olesen
Antibiotics 2020, 9(5), 239; https://doi.org/10.3390/antibiotics9050239 - 8 May 2020
Cited by 1 | Viewed by 2631
Abstract
For the past several decades, the success of bacterial strains in infecting their host has been essentially ascribed to the presence of canonical virulence genes. While it is unclear how much growth rate impacts the outcome of an infection, it is long known [...] Read more.
For the past several decades, the success of bacterial strains in infecting their host has been essentially ascribed to the presence of canonical virulence genes. While it is unclear how much growth rate impacts the outcome of an infection, it is long known that the efficacy of the most commonly used antibiotics is correlated to growth. This applies especially to β-lactams, whose efficacy is nearly abolished when cells grow very slowly. It is therefore reasonable to assume that a niche or genetic dependent change in growth rate could contribute to the variability in the outcome of antibiotic therapy. However, little is known about the growth rate of pathogens or their pathotypes in their host. Full article
(This article belongs to the Special Issue Antibiotic Targets in Bacterial DNA Replication and Cell Division)
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