Article
Chemistry, Medicinal
Maja Kokot, Marko Anderluh, Martina Hrast, Nikola Minovski
Summary: The emergence of bacterial resistance has created a need for new and effective antibacterial agents. Novel bacterial topoisomerase inhibitors (NBTIs) represent a promising class of antibacterial agents that can target different bacterial species with varying potencies.
JOURNAL OF MEDICINAL CHEMISTRY
(2022)
Article
Chemistry, Medicinal
Martina Durcik, Akos Nyerges, Ziga Skok, Darja Gramec Skledar, Jurij Trontelj, Nace Zidar, Janez Ilas, Anamarija Zega, Cristina D. Cruz, Paivi Tammela, Martin Welin, Yengo R. Kimbung, Dorota Focht, Ondrej Benek, Tamas Revesz, Gabor Draskovits, Petra Eva Szili, Lejla Daruka, Csaba Pal, Danijel Kikelj, Lucija Peterlin Masic, Tihomir Tomasic
Summary: The rise in multidrug-resistant bacteria highlights the need for new antibacterial agents less prone to resistance. Compounds simultaneously inhibiting multiple bacterial targets, like 31h, show promising antibacterial activities without cytotoxicity and potency against various pathogens, including those resistant to other drugs. The structural derivatives of 31h could represent a step towards clinically efficacious multitargeting antimicrobials resilient to existing antimicrobial resistance.
EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY
(2021)
Article
Microbiology
Dmitry Sutormin, Alina Galivondzhyan, Azamat Gafurov, Konstantin Severinov
Summary: Topoisomerase IV (Topo IV) is the primary decatenation enzyme in Escherichia coli, responsible for removing catenation links formed during DNA replication. Using a more sensitive Topo-Seq procedure, we identified thousands of Topo IV cleavage sites (TCSs) throughout the bacterial genome. The determined cleavage motif of Topo IV contained previously known cleavage determinants as well as some new positions. TCSs were found to be depleted in the Ter macrodomain, except for two exceptionally strong non-canonical cleavage sites near the dif-site.
FRONTIERS IN MICROBIOLOGY
(2023)
Review
Chemistry, Medicinal
Scott Grossman, Colin W. G. Fishwick, Martin J. McPhillie
Summary: Increases in antibiotic usage have led to antimicrobial resistance and reduced effectiveness of antimicrobial treatments. Researchers have been looking for new bioactive molecules to inhibit bacterial topoisomerases through non-intercalating agents and alternative mechanisms, such as allosteric site inhibitors and ATPase domain inhibitors, to overcome bacterial resistance to fluoroquinolones.
Article
Microbiology
Johanne Blais, Charles R. Dean, Guillaume Lapointe, Jennifer A. Leeds, Sylvia Ma, Laura Morris, Heinz E. Moser, Colin S. Osborne, Katherine R. Prosen, Daryl Richie, Colin Skepper, Katherine Thompson, Jason Vo, Qin Yue, Alexey Rivkin
Summary: CUO246 is a novel DNA gyrase/topoisomerase IV inhibitor with broad-spectrum in vitro activity against Gram-positive, fastidious Gram-negative, and atypical bacterial pathogens, including quinolone-resistant strains. It inhibits both DNA gyrase and topoisomerase IV and exhibits potent bactericidal activity. In a mouse model, it shows efficacy against S. aureus infections. CUO246 may be a useful treatment option for acute skin and skin structure infections, respiratory tract infections, and sexually transmitted infections.
ANTIMICROBIAL AGENTS AND CHEMOTHERAPY
(2022)
Article
Microbiology
Anna Olina, Aleksei Agapov, Denis Yudin, Dmitry Sutormin, Alina Galivondzhyan, Anton Kuzmenko, Konstantin Severinov, Alexei A. Aravin, Andrey Kulbachinskiy
Summary: This study demonstrates that two cyanobacterial pAgos, SeAgo and LrAgo, can assist DNA replication and facilitate cell division in the presence of topoisomerase inhibitors in Escherichia coli. They are specifically loaded with small guide DNAs derived from the replication termination region and protect the cells from the action of the gyrase inhibitor ciprofloxacin, suggesting that they help to complete DNA replication and/or repair gyrase-induced breaks.
MICROBIOLOGY SPECTRUM
(2023)
Article
Microbiology
Raimo Franke, Heike Overwin, Susanne Haeussler, Mark Broenstrup
Summary: The study demonstrates that three different classes of gyrase inhibitors can be distinguished by their molecular signatures in P. aeruginosa using transcriptomics and metabolomics. This indicates that inhibiting a complex target at different sites with different compounds may have similar or differentiated cellular consequences. The study results have implications for mode-of-action discovery approaches based on target-specific reference compounds, as they highlight the intraclass variability of cellular compound effects.
Article
Biochemistry & Molecular Biology
Soziema E. E. Dauda, Jessica A. A. Collins, Jo Ann W. Byl, Yanran Lu, Jack C. C. Yalowich, Mark J. J. Mitton-Fry, Neil Osheroff
Summary: Novel bacterial topoisomerase inhibitors (NBTIs) are a new class of antibiotics that target gyrase and topoisomerase IV. NBTIs can induce gyrase/topoisomerase IV-mediated single-stranded DNA breaks and suppress the generation of double-stranded breaks. However, some dioxane-linked amide NBTIs have been found to induce double-stranded DNA breaks mediated by Staphylococcus aureus gyrase. The compound OSUAB-185 induces single-stranded and suppressed double-stranded DNA breaks mediated by Neisseria gonorrhoeae gyrase, while stabilizing both single- and double-stranded DNA breaks mediated by topoisomerase IV.
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
(2023)
Article
Chemistry, Medicinal
Eddy E. Alfonso, Rogelio Troche, Zifang Deng, Thirunavukkarasu Annamalai, Prem Chapagain, Yuk-Ching Tse-Dinh, Fenfei Leng
Summary: The study identified effective bacterial DNA gyrase inhibitors that exhibit strong antimicrobial activities against E. coli and Staphylococcus aureus.
Review
Biochemistry & Molecular Biology
Charles J. Dorman
Summary: Transcription is a noisy and stochastic process that leads to variations in physiology among genetically identical cells due to transcription bursting and failure to remove accumulated supercoils in DNA. The relaxation of these supercoils is performed by type II topoisomerases, but interference with their action can disrupt transcription and lead to phenotypic outliers such as antibiotic-tolerant persister cells. This interference can also drive physiological diversity in the bacterial population as an important epigenetic factor.
MOLECULAR MICROBIOLOGY
(2023)
Article
Multidisciplinary Sciences
Han Wang, Guojun Chen, Hongbin Li
Summary: The folding of the RTX block-iv in adenylate cyclase is templated by the folded RTX block-v, which allows rapid folding and significant mutual stabilization. This finding provides insights into the mechanism of transmitting the folding signal within the RTX domain.
NATURE COMMUNICATIONS
(2022)
Article
Microbiology
Angela K. Talley, Archie Thurston, Grayson Moore, Vipul K. Gupta, Myriah Satterfield, Erika Manyak, Suzanne Stokes, Aaron Dane, David Melnick
Summary: SPR720, a novel bacterial DNA gyrase inhibitor, has shown promise in treating nontuberculous mycobacterial pulmonary disease and pulmonary tuberculosis. Clinical trial results demonstrate good tolerability of SPR720 at daily doses up to 1,000 mg for 14 days, with common adverse events being gastrointestinal discomfort and headache, and stable pharmacokinetic profile.
ANTIMICROBIAL AGENTS AND CHEMOTHERAPY
(2021)
Article
Biochemistry & Molecular Biology
Rupesh Kumar, Soon Bahng, Kenneth J. Marians
Summary: The bacterial condensin MukB and the cellular chromosomal decatenase, topoisomerase IV interact and stimulate each other's activity in DNA condensation, while in stoichiometric complexes of the two enzymes they inhibit each other and provide a stable scaffold for chromosomal DNA condensation.
NUCLEIC ACIDS RESEARCH
(2022)
Article
Chemistry, Medicinal
Firas O. A. Frejat, Yaquan Cao, Lihong Wang, Hongjin Zhai, Ahmed H. Abdelazeem, Hesham A. M. Gomaa, Bahaa G. M. Youssif, Chunli Wu
Summary: A series of hybridized pyrrolidine compounds with a 1,2,4-oxadiazole moiety were synthesized as potential inhibitors against DNA gyrase and topoisomerase IV. Compounds 16 and 17 showed the strongest inhibitory effects against both enzymes, with compound 17 outperforming novobiocin in MIC assays against E. coli. The results of this study support the promising approach of developing potent leads for further optimization.
ARCHIV DER PHARMAZIE
(2022)
Article
Chemistry, Medicinal
Martina Durcik, Andrej Emanuel Cotman, Zan Toplak, Stefan Mozina, Ziga Skok, Petra Eva Szili, Marton Czikkely, Elvin Maharramov, Thu Hien Vu, Maria Vittoria Piras, Nace Zidar, Janez Ilas, Anamarija Zega, Jurij Trontelj, Luis A. Pardo, Diarmaid Hughes, Douglas Huseby, Talia Berruga-Fernandez, Sha Cao, Ivailo Simoff, Richard Svensson, Sergiy V. Korol, Zhe Jin, Francisca Vicente, Maria C. Ramos, Julia E. A. Mundy, Anthony Maxwell, Clare E. M. Stevenson, David M. Lawson, Bjorn Glinghammar, Eva Sjostrom, Martin Bohlin, Joanna Oreskar, Sofie Alver, Guido V. Janssen, Geert Jan Sterk, Danijel Kikelj, Csaba Pal, Tihomir Tomasic, Lucija Peterlin Masic
Summary: A new series of dual low nanomolar benzothiazole inhibitors of bacterial DNA gyrase and topoisomerase IV were developed, exhibiting broad-spectrum antibacterial activities against various strains. Lead compound 7a showed favorable properties and selectivity for bacterial topoisomerases, and demonstrated efficacy in vivo.
JOURNAL OF MEDICINAL CHEMISTRY
(2023)
Article
Multidisciplinary Sciences
Nikolaus Dietz, Markus Huber, Isabel Sorg, Arnaud Goepfert, Alexander Harms, Tilman Schirmer, Christoph Dehio
Summary: The bacterial effector protein Bep1 selectively targets members of the Rac subfamily in the Rho family of small GTPases based on electrostatic interactions, providing a highly selective tool for functional analysis of these GTPases. This study establishes a structural understanding of target selectivity towards Rac-subfamily GTPases.
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
(2021)
Article
Microbiology
Tilman Schirmer, Tjaart A. P. de Beer, Stefanie Tamegger, Alexander Harms, Nikolaus Dietz, David M. Dranow, Thomas E. Edwards, Peter J. Myler, Isabelle Phan, Christoph Dehio
Summary: This study elucidates the expansion and diversification of FIC domains in the Bartonella Bep repertoire using X-ray crystallography, structural modeling, and phylogenetic analysis. The findings reveal remarkable functional plasticity of Beps primarily due to structural changes in the substrate pocket and the target dock. These insights may guide future structure-function analyses of these highly versatile FIC domains.
Editorial Material
Biochemistry & Molecular Biology
Enea Maffei, Alexander Harms
Summary: Bacteria killed by viruses release a warning signal that induces neighboring cells to enhance their defenses, resulting in phenotypic tolerance to infections and slowing down viral spread in the population.
Article
Multidisciplinary Sciences
Marco Herfurth, Anke Treuner-Lange, Timo Glatter, Nadine Wittmaack, Egbert Hoiczyk, Antonio J. Pierik, Lotte Sogaard-Andersen
Summary: The study reveals the formation of complexes between minor pilins and PilY1.1, contingent on calcium and a non-canonical cytochrome c, in Myxococcus xanthus. This discovery highlights the importance of these complexes in stabilizing PilY1.1 and enabling T4aP function in a broader range of calcium concentrations.
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
(2022)
Article
Biochemistry & Molecular Biology
Enea Maffei, Aisylu Shaidullina, Marco Burkolter, Yannik Heyer, Fabienne Estermann, Valentin Druelle, Patrick Sauer, Luc Willi, Sarah Michaelis, Hubert Hilbi, David S. Thaler, Alexander Harms
Summary: This study aimed to promote a systematic exploration of phage-host interactions by establishing a phage sample library. The research characterized 68 phages phenotypically and genomically, identified essential host receptors, quantified their sensitivity to different bacterial defense systems, and revealed systematic differences in potency among immunity systems and molecular basis of receptor specificity in various phage groups. Results also indicated trade-offs between fitness traits that might drive divergent adaptation of different phage groups to specific ecological niches. The BASEL collection is envisioned to inspire future research in the biology of bacteriophages and hosts for effective translation into biotechnology or therapeutic applications.
Editorial Material
Biochemistry & Molecular Biology
Aisylu Shaidullina, Alexander Harms
Summary: This study reveals how the DNA-targeting ADP-ribosylation activity of toxin-antitoxin systems impairs phage replication and the emergence of viral inhibitors that overcome this inhibition.
TRENDS IN MICROBIOLOGY
(2022)
Article
Multidisciplinary Sciences
Selen Manioglu, Seyed Majed Modaresi, Noah Ritzmann, Johannes Thoma, Sarah A. Overall, Alexander Harms, Gregory Upert, Anatol Luther, Alexander B. Barnes, Daniel Obrecht, Daniel J. Muller, Sebastian Hiller
Summary: The study uses high-resolution atomic force microscopy to investigate the interaction mechanism between Polymyxins and bacterial membranes. The results show that Polymyxins can arrange bacterial lipids into regular hexagonal structures, making the membrane stiffer and leading to rupture.
NATURE COMMUNICATIONS
(2022)
Article
Biochemical Research Methods
Tania S. Koebel, Rafael Melo Palhares, Christin Fromm, Witold Szymanski, Georgia Angelidou, Timo Glatter, Jens Georg, Bork A. Berghoff, Daniel Schindler
Summary: Synthetic biology approaches life as an engineer, using standardized and de novo design of genetic parts to build reproducible and controllable modules. Regulatory RNAs play a crucial role in bacteria, and synthetic sRNAs have broad applications in synthetic biology.
ACS SYNTHETIC BIOLOGY
(2022)
Review
Microbiology
Aisylu Shaidullina, Alexander Harms
Summary: Bacteriophages are important predators in ecosystems with potential applications in biotechnology and bacterial infection treatment. Advances in sequencing and genome-wide screens allow for systematic study of phage-host interactions, paving the way for future applications and research expansion.
CURRENT OPINION IN MICROBIOLOGY
(2022)
Editorial Material
Microbiology
Alexander Harms, Martin J. Loessner
CURRENT OPINION IN MICROBIOLOGY
(2023)
Article
Plant Sciences
Paul Weiland, Felix Dempwolff, Wieland Steinchen, Sven-Andreas Freibert, Hui Tian, Timo Glatter, Roman Martin, Bart P. H. J. Thomma, Gert Bange, Florian Altegoer
Summary: Plant-pathogenic fungi play a major role in causing plant diseases and crop loss. In this study, the atomic structures of Cpl1 and Uvi2 proteins from Ustilago maydis and Ustilago hordei were determined. These proteins adopt a unique double-ψβ-barrel architecture and bind to chitin fragments in a novel mode. Cpl1 localizes to the cell wall of U. maydis and might coordinate with other cell wall-degrading and decorating proteins during maize infection. Deletion of uvi2 significantly impairs U. hordei virulence, indicating a diverging function from Cpl1.
MOLECULAR PLANT PATHOLOGY
(2023)
Article
Multidisciplinary Sciences
Maik Wolfram-Schauerte, Nadiia Pozhydaieva, Julia Grawenhoff, Luisa M. Welp, Ivan Silbern, Alexander Wulf, Franziska A. Billau, Timo Glatter, Henning Urlaub, Andres Jaeschke, Katharina Hoefer
Summary: Viral infections involve the use of ARTs to reprogram the host's genetic machinery, and this study shows that ModB can attach entire RNA chains to acceptor proteins in an 'RNAylation' reaction. ModB specifically attaches selected RNAs to ribosomal proteins, providing a mechanism for the phage to modulate the host's translation machinery. This work reveals a direct connection between RNA modification and post-translational protein modification.
Article
Multidisciplinary Sciences
Adrian Izquierdo-Martinez, Maria Billini, Vega Miguel-Ruano, Rogelio Hernandez-Tamayo, Pia Richter, Jacob Biboy, Maria T. Batuecas, Timo Glatter, Waldemar Vollmer, Peter L. Graumann, Juan A. Hermoso, Martin Thanbichler
Summary: This study demonstrates that a protein called DipM coordinates different peptidoglycan-remodeling pathways to regulate cell wall-degrading enzymes, ensuring proper cell constriction and daughter cell separation in bacteria.
NATURE COMMUNICATIONS
(2023)
Article
Biochemical Research Methods
Marco Herfurth, Franziska Mueller, Lotte Sogaard-Andersen, Timo Glatter
Summary: This protocol provides detailed instructions on how to identify stable and transient protein interactomes in bacteria using biotin ligase miniTurbo-based proximity labeling, including steps for control protein expression optimization, biotin labeling of bacteria, enrichment of biotinylated proteins, and sample processing for proteomic analysis.
Article
Microbiology
Benjamin Sellner, Ruta Prakapaite, Margo van Berkum, Matthias Heinemann, Alexander Harms, Urs Jenal
Summary: Bacteriophage N4 uses a novel surface glycan as a receptor to infect E. coli, with the process regulated by the second messenger c-di-GMP and specific enzymes DgcJ and PdeL. The protection mechanism mediated by PdeL involves reducing c-di-GMP and repressing the wec operon, which serves as a receptor for N4.
