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Antibiotics
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Bacterial DNA Replication and Replication Inhibitors
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Bacterial DNA Replication and Replication Inhibitors

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

Deadline for manuscript submissions: closed (30 November 2017) | Viewed by 49852

Special Issue Editor

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

Special Issue Information

Dear Colleagues,

This Special Issue of Antibiotics is dedicated to the topic of "Bacterial DNA Replication and Replication Inhibitors". 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 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.

This Special Issue will summarize the current knowledge on bacterial DNA replication and its 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, its regulation and inhibition by established drugs and novel inhibitors.

Prof. Dr. Anders Løbner-Olesen
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. 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
  • replication control
  • replication enzymes
  • initiation, elongation and termination of replication
  • replisome, function and processivity
  • protein-protein interactions
  • inhibition
  • antimicrobials
  • antibiotic resistance

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Published Papers (7 papers)

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Research

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16 pages, 5344 KiB  
Article
Complementation Studies of Bacteriophage λ O Amber Mutants by Allelic Forms of O Expressed from Plasmid, and O-P Interaction Phenotypes
by Sidney Hayes, Karthic Rajamanickam and Connie Hayes
Antibiotics 2018, 7(2), 31; https://doi.org/10.3390/antibiotics7020031 - 5 Apr 2018
Cited by 2 | Viewed by 5487
Abstract
λ genes O and P are required for replication initiation from the bacteriophage λ origin site, oriλ, located within gene O. Questions have persisted for years about whether O-defects can indeed be complemented in trans. We show the effect of [...] Read more.
λ genes O and P are required for replication initiation from the bacteriophage λ origin site, oriλ, located within gene O. Questions have persisted for years about whether O-defects can indeed be complemented in trans. We show the effect of original null mutations in O and the influence of four origin mutations (three are in-frame deletions and one is a point mutation) on complementation. This is the first demonstration that O proteins with internal deletions can complement for O activity, and that expression of the N-terminal portion of gene P can completely prevent O complementation. We show that O-P co-expression can limit the lethal effect of P on cell growth. We explore the influence of the contiguous small RNA OOP on O complementation and P-lethality. Full article
(This article belongs to the Special Issue Bacterial DNA Replication and Replication Inhibitors)
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12 pages, 6193 KiB  
Article
Fragment-Based Discovery of Inhibitors of the Bacterial DnaG-SSB Interaction
by Zorik Chilingaryan, Stephen J. Headey, Allen T. Y. Lo, Zhi-Qiang Xu, Gottfried Otting, Nicholas E. Dixon, Martin J. Scanlon and Aaron J. Oakley
Antibiotics 2018, 7(1), 14; https://doi.org/10.3390/antibiotics7010014 - 22 Feb 2018
Cited by 14 | Viewed by 4965
Abstract
In bacteria, the DnaG primase is responsible for synthesis of short RNA primers used to initiate chain extension by replicative DNA polymerase(s) during chromosomal replication. Among the proteins with which Escherichia coli DnaG interacts is the single-stranded DNA-binding protein, SSB. The C-terminal hexapeptide [...] Read more.
In bacteria, the DnaG primase is responsible for synthesis of short RNA primers used to initiate chain extension by replicative DNA polymerase(s) during chromosomal replication. Among the proteins with which Escherichia coli DnaG interacts is the single-stranded DNA-binding protein, SSB. The C-terminal hexapeptide motif of SSB (DDDIPF; SSB-Ct) is highly conserved and is known to engage in essential interactions with many proteins in nucleic acid metabolism, including primase. Here, fragment-based screening by saturation-transfer difference nuclear magnetic resonance (STD-NMR) and surface plasmon resonance assays identified inhibitors of the primase/SSB-Ct interaction. Hits were shown to bind to the SSB-Ct-binding site using 15N–1H HSQC spectra. STD-NMR was used to demonstrate binding of one hit to other SSB-Ct binding partners, confirming the possibility of simultaneous inhibition of multiple protein/SSB interactions. The fragment molecules represent promising scaffolds on which to build to discover new antibacterial compounds. Full article
(This article belongs to the Special Issue Bacterial DNA Replication and Replication Inhibitors)
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14 pages, 3590 KiB  
Article
Screening of E. coli β-clamp Inhibitors Revealed that Few Inhibit Helicobacter pylori More Effectively: Structural and Functional Characterization
by Preeti Pandey, Vijay Verma, Suman Kumar Dhar and Samudrala Gourinath
Antibiotics 2018, 7(1), 5; https://doi.org/10.3390/antibiotics7010005 - 11 Jan 2018
Cited by 3 | Viewed by 4973
Abstract
The characteristic of interaction with various enzymes and processivity-promoting nature during DNA replication makes β-clamp an important drug target. Helicobacter pylori (H. pylori) have several unique features in DNA replication machinery that makes it different from other microorganisms. To find out [...] Read more.
The characteristic of interaction with various enzymes and processivity-promoting nature during DNA replication makes β-clamp an important drug target. Helicobacter pylori (H. pylori) have several unique features in DNA replication machinery that makes it different from other microorganisms. To find out whether difference in DNA replication proteins behavior accounts for any difference in drug response when compared to E. coli, in the present study, we have tested E. coli β-clamp inhibitor molecules against H. pylori β-clamp. Various approaches were used to test the binding of inhibitors to H. pylori β-clamp including docking, surface competition assay, complex structure determination, as well as antimicrobial assay. Out of five shortlisted inhibitor molecules on the basis of docking score, three molecules, 5-chloroisatin, carprofen, and 3,4-difluorobenzamide were co-crystallized with H. pylori β-clamp and the structures show that they bind at the protein-protein interaction site as expected. In vivo studies showed only two molecules, 5-chloroisatin, and 3,4-difluorobenzamide inhibited the growth of the pylori with MIC values in micro molar range, which is better than the inhibitory effect of the same drugs on E. coli. Therefore, the evaluation of such drugs against H. pylori may explore the possibility to use to generate species-specific pharmacophore for development of new drugs against H. pylori. Full article
(This article belongs to the Special Issue Bacterial DNA Replication and Replication Inhibitors)
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3523 KiB  
Article
Establishing a System for Testing Replication Inhibition of the Vibrio cholerae Secondary Chromosome in Escherichia coli
by Nadine Schallopp, Sarah Milbredt, Theodor Sperlea, Franziska S. Kemter, Matthias Bruhn, Daniel Schindler and Torsten Waldminghaus
Antibiotics 2018, 7(1), 3; https://doi.org/10.3390/antibiotics7010003 - 23 Dec 2017
Cited by 9 | Viewed by 6030
Abstract
Regulators of DNA replication in bacteria are an attractive target for new antibiotics, as not only is replication essential for cell viability, but its underlying mechanisms also differ from those operating in eukaryotes. The genetic information of most bacteria is encoded on a [...] Read more.
Regulators of DNA replication in bacteria are an attractive target for new antibiotics, as not only is replication essential for cell viability, but its underlying mechanisms also differ from those operating in eukaryotes. The genetic information of most bacteria is encoded on a single chromosome, but about 10% of species carry a split genome spanning multiple chromosomes. The best studied bacterium in this context is the human pathogen Vibrio cholerae, with a primary chromosome (Chr1) of 3 M bps, and a secondary one (Chr2) of about 1 M bps. Replication of Chr2 is under control of a unique mechanism, presenting a potential target in the development of V. cholerae-specific antibiotics. A common challenge in such endeavors is whether the effects of candidate chemicals can be focused on specific mechanisms, such as DNA replication. To test the specificity of antimicrobial substances independent of other features of the V. cholerae cell for the replication mechanism of the V. cholerae secondary chromosome, we establish the replication machinery in the heterologous E. coli system. We characterize an E. coli strain in which chromosomal replication is driven by the replication origin of V. cholerae Chr2. Surprisingly, the E. coli ori2 strain was not inhibited by vibrepin, previously found to inhibit ori2-based replication. Full article
(This article belongs to the Special Issue Bacterial DNA Replication and Replication Inhibitors)
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Review

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19 pages, 3993 KiB  
Review
DnaG Primase—A Target for the Development of Novel Antibacterial Agents
by Stefan Ilic, Shira Cohen, Meenakshi Singh, Benjamin Tam, Adi Dayan and Barak Akabayov
Antibiotics 2018, 7(3), 72; https://doi.org/10.3390/antibiotics7030072 - 13 Aug 2018
Cited by 17 | Viewed by 11114
Abstract
The bacterial primase—an essential component in the replisome—is a promising but underexploited target for novel antibiotic drugs. Bacterial primases have a markedly different structure than the human primase. Inhibition of primase activity is expected to selectively halt bacterial DNA replication. Evidence is growing [...] Read more.
The bacterial primase—an essential component in the replisome—is a promising but underexploited target for novel antibiotic drugs. Bacterial primases have a markedly different structure than the human primase. Inhibition of primase activity is expected to selectively halt bacterial DNA replication. Evidence is growing that halting DNA replication has a bacteriocidal effect. Therefore, inhibitors of DNA primase could provide antibiotic agents. Compounds that inhibit bacterial DnaG primase have been developed using different approaches. In this paper, we provide an overview of the current literature on DNA primases as novel drug targets and the methods used to find their inhibitors. Although few inhibitors have been identified, there are still challenges to develop inhibitors that can efficiently halt DNA replication and may be applied in a clinical setting. Full article
(This article belongs to the Special Issue Bacterial DNA Replication and Replication Inhibitors)
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8 pages, 262 KiB  
Review
Our Evolving Understanding of the Mechanism of Quinolones
by Arnaud Gutierrez, Jonathan M. Stokes and Ivan Matic
Antibiotics 2018, 7(2), 32; https://doi.org/10.3390/antibiotics7020032 - 8 Apr 2018
Cited by 28 | Viewed by 7001
Abstract
The maintenance of DNA supercoiling is essential for the proper regulation of a plethora of biological processes. As a consequence of this mode of regulation, ahead of the replication fork, DNA replication machinery is prone to introducing supercoiled regions into the DNA double [...] Read more.
The maintenance of DNA supercoiling is essential for the proper regulation of a plethora of biological processes. As a consequence of this mode of regulation, ahead of the replication fork, DNA replication machinery is prone to introducing supercoiled regions into the DNA double helix. Resolution of DNA supercoiling is essential to maintain DNA replication rates that are amenable to life. This resolution is handled by evolutionarily conserved enzymes known as topoisomerases. The activity of topoisomerases is essential, and therefore constitutes a prime candidate for targeting by antibiotics. In this review, we present hallmark investigations describing the mode of action of quinolones, one of the antibacterial classes targeting the function of topoisomerases in bacteria. By chronologically analyzing data gathered on the mode of action of this imperative antibiotic class, we highlight the necessity to look beyond primary drug-target interactions towards thoroughly understanding the mechanism of quinolones at the level of the cell. Full article
(This article belongs to the Special Issue Bacterial DNA Replication and Replication Inhibitors)
28 pages, 1054 KiB  
Review
The Macromolecular Machines that Duplicate the Escherichia coli Chromosome as Targets for Drug Discovery
by Jon M. Kaguni
Antibiotics 2018, 7(1), 23; https://doi.org/10.3390/antibiotics7010023 - 14 Mar 2018
Cited by 17 | Viewed by 7541
Abstract
DNA replication is an essential process. Although the fundamental strategies to duplicate chromosomes are similar in all free-living organisms, the enzymes of the three domains of life that perform similar functions in DNA replication differ in amino acid sequence and their three-dimensional structures. [...] Read more.
DNA replication is an essential process. Although the fundamental strategies to duplicate chromosomes are similar in all free-living organisms, the enzymes of the three domains of life that perform similar functions in DNA replication differ in amino acid sequence and their three-dimensional structures. Moreover, the respective proteins generally utilize different enzymatic mechanisms. Hence, the replication proteins that are highly conserved among bacterial species are attractive targets to develop novel antibiotics as the compounds are unlikely to demonstrate off-target effects. For those proteins that differ among bacteria, compounds that are species-specific may be found. Escherichia coli has been developed as a model system to study DNA replication, serving as a benchmark for comparison. This review summarizes the functions of individual E. coli proteins, and the compounds that inhibit them. Full article
(This article belongs to the Special Issue Bacterial DNA Replication and Replication Inhibitors)
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