Review
Biochemistry & Molecular Biology
Holly M. M. Radford, Casey J. J. Toft, Alanna E. E. Sorenson, Patrick M. M. Schaeffer
Summary: Over 1.2 million deaths are caused by multi-drug-resistant bacteria each year, as a result of their fast replication and rapid evolution. The accumulation of resistance genes in pathogens has made current antibiotic treatments ineffective, leading to a decrease in reliable treatment options for MDR-associated diseases. This review provides a critical evaluation of DNA replication initiation in bacteria and highlights the potential of essential initiation proteins as emerging drug targets. It also examines the available methods to study and screen promising replication initiation proteins.
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
(2023)
Review
Cell Biology
Marina A. Bellani, Althaf Shaik, Ishani Majumdar, Chen Ling, Michael M. Seidman
Summary: The replication apparatus faces challenges in duplicating the genome, particularly when encountering covalent DNA adducts on the leading template strand. The helicase, a key component of the replication machinery, is responsible for unwinding DNA and coming into contact with the adducts. Recent studies have shown that the helicase is able to tolerate larger adducts than previously believed.
Article
Microbiology
Bin-Bin Xie, Jin-Cheng Rong, Bai-Lu Tang, Sishuo Wang, Guiming Liu, Qi-Long Qin, Xi-Ying Zhang, Weipeng Zhang, Qunxin She, Yin Chen, Fuchuan Li, Shengying Li, Xiu-Lan Chen, Haiwei Luo, Yu-Zhong Zhang
Summary: Chromosome replication is essential for cell division, with bidirectional replication being the rule for bacterial chromosomes. In Pseudoalteromonas, chromids can replicate either unidirectionally or bidirectionally, indicating a single evolutionary transition from unidirectionality to bidirectionality. This study sheds light on the physiological aspects of chromosome replication and the early evolutionary history of bacterial chromosomes.
Article
Biochemistry & Molecular Biology
Thomas A. Guilliam, Joseph T. P. Yeeles
Summary: The study shows that a yeast replisome is inherently tolerant to the oxidative lesion Tg, efficiently bypassing leading-strand Tg even in the absence of TLS machinery. A switch from Pol epsilon to Pol delta after helicase-polymerase uncoupling promotes rapid, efficient, and error-free lesion bypass at physiological nucleotide levels. Replicase switching may facilitate continued leading-strand synthesis when Pol delta is more effective at bypassing damage than Pol epsilon.
Article
Biology
Po Jui Chen, Anna B. McMullin, Bryan J. Visser, Qian Mei, Susan M. Rosenberg, David Bates
Summary: In bacteria, sister replisomes are functionally interdependent and remain colocalized throughout replication. Our study reveals the crucial role of physical association between sister replisomes in ensuring an efficient and uninterrupted replication program.
Article
Biochemistry & Molecular Biology
Kyle B. Vrtis, James M. Dewar, Gheorghe Chistol, R. Alex Wu, Thomas G. W. Graham, Johannes C. Walter
Summary: Research has shown that collisions between the replicative CMG helicase and nicks in DNA templates can lead to different forms of double-strand breaks, causing replisome disassembly.
Review
Biochemistry & Molecular Biology
Thomas A. Guilliam
Summary: The eukaryotic replisome encounters obstacles such as damaged and structured DNA during replication, but various mechanisms exist to overcome these hurdles, maintain progression, and prevent fork collapse. Recent advances in structural, biochemical, and single-molecule approaches have enhanced our understanding of the replisome's architecture, response to impediments, and DNA damage tolerance mechanisms.
FRONTIERS IN MOLECULAR BIOSCIENCES
(2021)
Article
Biology
Deepak Bhat, Samuel Hauf, Charles Plessy, Yohei Yokobayashi, Simone Pigolotti, Armita Nourmohammad
Summary: In this study, a new method was proposed to infer the dynamics of Replisomes from DNA abundance distribution. The method was applied to measure the DNA abundance distribution in Escherichia coli populations growing at different temperatures. The results showed that the speed of Replisomes increases with temperature and exhibits wave-like variations along the genome, which correlates with the variation of mutation rate. This study provides insights into the replication dynamics of bacteria.
Article
Biochemistry & Molecular Biology
Yoshitami Hashimoto, Kota Sadano, Nene Miyata, Haruka Ito, Hirofumi Tanaka
Summary: DONSON is a novel initiator protein essential for CMG helicase assembly in vertebrates, as demonstrated by experiments in a Xenopus cell-free system. DONSON interacts with GINS and Pol ε to promote replisome assembly, and its chromatin association during replication initiation requires the pre-replicative complex, TopBP1, and kinase activities of S-CDK and DDK.
Article
Chemistry, Medicinal
Clement Monsarrat, Guillaume Compain, Christophe Andre, Sylvain Engilberge, Isabelle Martiel, Vincent Olieric, Philippe Wolff, Karl Brillet, Marie Landolfo, Cyrielle Silva da Veiga, Jerome Wagner, Gilles Guichard, Dominique Y. Burnouf
Summary: A study was conducted on a series of peptides interacting with the Escherichia coli SC binding pocket, showing improved affinity through various modifications. X-ray structure analysis revealed new peptide-protein interactions that explained the enhanced binding mechanism.
JOURNAL OF MEDICINAL CHEMISTRY
(2021)
Review
Cell Biology
Janne J. M. van Schie, Job de Lange
Summary: The cohesin complex plays a vital role in accurate chromosome segregation by pairing sister chromatids and assisting in error-free DNA replication. The processes of replisome progression and establishment of sister chromatid cohesion are closely linked. Understanding how key factors in DNA replication and cohesion establishment cooperate under normal and stressed conditions is crucial for studying genome stability.
Review
Biochemistry & Molecular Biology
Rebeca Bocanegra, Ismael G. A. Plaza, Carlos R. Pulido, Borja Ibarra
Summary: The study reveals that the replisome machinery is stochastic, versatile, and highly dynamic, with transient protein-protein and protein-DNA interactions playing a key role in robust DNA replication.
COMPUTATIONAL AND STRUCTURAL BIOTECHNOLOGY JOURNAL
(2021)
Article
Biochemistry & Molecular Biology
Morgan L. Jones, Yasemin Baris, Martin R. G. Taylor, Joseph T. P. Yeeles
Summary: This study determined the structure of a human replisome containing multiple proteins, revealing their interactions and providing insights into the working mechanism of the replisome and how it maintains smooth replication progression.
Article
Biology
Charanya Kumar, Sahil Batra, Jack D. Griffith, Dirk Remus
Summary: R-loops can lead to replication stress, but the impact can be suppressed by RNase H1 and Pif1. Replisomes have the ability to maintain fork progression in certain conditions, providing a mechanistic basis for distinguishing harmful from non-harmful R-loops.
Article
Microbiology
Nora Halgasova, Rachel Javorova, Lucia Bocanova, Daniela Krajcikova, Jacob A. Bauer, Gabriela Bukovska
Summary: The bacteriophage phiBP contains putative replisome organizer, helicase loader, and beta clamp that may play a role in DNA replication. Bioinformatics analysis found that the phiBP replisome organizer belongs to a newly identified family of initiator proteins. Recombinant proteins gpRO-HC and gpRO-HCK8A, with a lysine to alanine substitution at position 8, were prepared and studied. gpRO-HC showed low ATPase activity, regardless of DNA presence, while the mutant demonstrated significantly higher ATPase activity. gpRO-HC bound to both single- and double-stranded DNA substrates, forming higher oligomers composed of about 12 subunits. This study provides valuable information on phage initiator proteins involved in DNA replication in low GC Gram-positive bacteria.
MICROBIOLOGICAL RESEARCH
(2023)
Article
Chemistry, Multidisciplinary
Sangeun Lee, Sarah Nasr, Sari Rasheed, Yun Liu, Olga Hartwig, Cansu Kaya, Annette Boese, Marcus Koch, Jennifer Herrmann, Rolf Mueller, Brigitta Loretz, Eric Buhler, Anna K. H. Hirsch, Claus-Michael Lehr
Summary: The recent success of mRNA vaccines using lipid-based vectors highlights the importance of strategies for nucleotide delivery under the pandemic situation. Although current mRNA delivery is focused on lipid-based vectors, still they need to be optimized for increasing stability, targeting, and efficiency, and for reducing toxicity. In this regard, other vector systems featuring smart strategies such as pH-responsive degradability and endosomal escape ability hold the potential to overcome the current limitations.
JOURNAL OF CONTROLLED RELEASE
(2023)
Article
Immunology
Marieke M. Kuijk, Yongzheng Wu, Vincent P. van Hensbergen, Gizem Shanlitourk, Christine Payre, Gerard Lambeau, Sandra Man-Bovenkerk, Jennifer Herrmann, Rolf Mueller, Jos A. G. van Strijp, Yvonne Pannekoek, Lhousseine Touqui, Nina M. van Sorge
Summary: Methicillin-resistant Staphylococcus aureus (MRSA) is a high priority pathogen that requires new treatments. Human group IIA-secreted phospholipase A(2) (hGIIA) is effective against MRSA infections. The study investigated the mechanisms of hGIIA resistance in MRSA and identified the lipoprotein signal peptidase LspA as a new resistance gene. LspA deletion also increased susceptibility to the antibiotic daptomycin.
JOURNAL OF INNATE IMMUNITY
(2023)
Article
Chemistry, Multidisciplinary
Timm O. Koller, Ullrich Scheid, Teresa Koesel, Jennifer Herrmann, Daniel Krug, Helena I. M. Boshoff, Bertrand Beckert, Joanna C. Evans, Jan Schlemmer, Becky Sloan, Danielle M. Weiner, Laura E. Via, Atica Moosa, Thomas R. Ioerger, Michael Graf, Boris Zinshteyn, Maha Abdelshahid, Fabian Nguyen, Stefan Arenz, Franziska Gille, Maik Siebke, Tim Seedorf, Oliver Plettenburg, Rachel Green, Anna-Luisa Warnke, Joachim Ullrich, Ralf Warrass, Clifton E. Barry, Digby F. Warner, Valerie Mizrahi, Andreas Kirschning, Daniel N. Wilson, Rolf Mueller
Summary: The resistance of bacterial pathogens against antibiotics is a major global health threat according to the WHO. The myxobacterial antibiotic myxovalargin has been found to be highly effective against Mycobacterium tuberculosis. Detailed study of myxovalargin biosynthesis has enabled the production of this compound through fermentation. Functional genomics analysis and feeding experiments have suggested a structural revision, which was confirmed through the development of a concise total synthesis.
JOURNAL OF THE AMERICAN CHEMICAL SOCIETY
(2023)
Article
Biochemistry & Molecular Biology
Yunsheng Gao, Christine Walt, Chantal D. Bader, Rolf Mueller
Summary: An unprecedented myxobacterial siderophore called sorangibactin was discovered in this study by heterologous expression of a coelibactin-like nonribosomal peptide synthetase (NRPS) gene cluster in a host strain. The structure of sorangibactin was found to be a linear polycyclic structure with multiple rings and functional groups. The study also revealed an unusual release mechanism involving a thioesterase (TE) domain, which can be further investigated for biochemically detailed studies.
ACS CHEMICAL BIOLOGY
(2023)
Article
Microbiology
Arne Bublitz, Madita Brauer, Stefanie Wagner, Walter Hofer, Mathias Musken, Felix Deschner, Till R. Lesker, Meina Neumann-Schaal, Lena -Sophie Paul, Ulrich Nubel, Jurgen Bartel, Andreas M. Kany, Daniela Zuhlke, Steffen Bernecker, Rolf Jansen, Susanne Sievers, Katharina Riedel, Jennifer Herrmann, Rolf Mueller, Thilo M. Fuchs, Till Strowig
Summary: Clostridium difficile infections (CDIs) are a significant healthcare problem, mainly due to high rates of relapsing/recurrent CDIs (rCDIs). In this study, the antimicrobial activity of chlorotonils against C. difficile is demonstrated. Chlorotonil A (ChA) effectively inhibits disease and prevents rCDI in mice, with minimal impact on the microbiota and intestinal metabolome. ChA also accumulates in the spore and inhibits outgrowth, potentially reducing rates of rCDI. These findings suggest that chlorotonils have unique antimicrobial properties targeting critical steps in the infection cycle of C. difficile.
CELL HOST & MICROBE
(2023)
Article
Infectious Diseases
Lais Pessanha de Carvalho, Elena Niepoth, Arbreshe Mavraj-Husejni, Andrea Kreidenweiss, Jennifer Herrmann, Rolf Mueller, Tanja Knaab, Bjoern B. Burckhardt, Thomas Kurz, Jana Held
Summary: In the absence of an effective vaccine, chemotherapy remains crucial for controlling malaria. The emergence of drug-resistant parasites emphasizes the need for new antimalarial drugs with improved properties. A sandwich enzyme-linked immunosorbent assay that detects the presence of Plasmodium falciparum histidine-rich protein 2 (HRP-2) was developed as an alternative to assess the parasite reduction ratio (PRR). The assay showed comparable results to the traditional method of measuring [3H]hypoxanthine incorporation. Rating: 7/10.
INTERNATIONAL JOURNAL OF ANTIMICROBIAL AGENTS
(2023)
Article
Biochemistry & Molecular Biology
Yu Mi Park, Markus R. Meyer, Rolf Mueller, Jennifer Herrmann
Summary: Zebrafish larvae have been established as a suitable in vivo model for drug metabolism studies. In this study, we focused on developing mass spectrometry imaging (MSI) protocols to investigate the spatial distribution of drugs and metabolites in zebrafish larvae. By studying the metabolism of naloxone, an opioid antagonist, we found that the zebrafish larvae model showed similar metabolites as human cells and other animal models. Furthermore, we successfully obtained MS images of naloxone and its metabolites in zebrafish larvae using optimized sample preparation procedures.
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
(2023)
Article
Plant Sciences
Sergi H. Akone, Joachim J. Hug, Amninder Kaur, Ronald Garcia, Rolf Mueller
Summary: The study reports the discovery, isolation, structure elucidation, and biological evaluation of two new bacterial sterols, nannosterols A and B, from the terrestrial myxobacterium Nannocystis sp. These nannosterols features unique modifications and chemical features, such as a secondary alcohol group at position C-15 and a terminal vicinal diol side chain at C-24-C-25, which have not been observed in bacterial sterols before. The investigation based on myxobacterial high-resolution secondary metabolome data and genomic in silico investigations revealed that nannosterols are frequently produced sterols within the myxobacterial suborder of Nannocystineae. The discovery of nannosterols provides insights into the biosynthesis and evolution of sterols by prokaryotes.
JOURNAL OF NATURAL PRODUCTS
(2023)
Article
Multidisciplinary Sciences
Philip Schippers, Sari Rasheed, Yu Mi Park, Timo Risch, Lea Wagmann, Selina Hemmer, Sascha K. Manier, Rolf Mueller, Jennifer Herrmann, Markus R. Meyer
Summary: This study compared six different extraction procedures to find the most suitable one for extracting zebrafish larvae in the context of an infection model. The two-phase methods (III and IV) resulted in a lower feature count, higher peak areas of interest (MoInt), especially amino acids, and higher coefficients of variation. Adding bead homogenization increased the feature count, peak areas, and CVs. Extraction I showed higher peak areas and lower CVs than extraction II, making it the most suitable one-phase method. Extraction III and IV showed similar results, with III being easier to execute and less prone to imprecisions. Thus, extractions I and III might be chosen for future applications in zebrafish larvae metabolomics and infection models.
SCIENTIFIC REPORTS
(2023)
Article
Biochemical Research Methods
Zong-Jie Wang, Xiaotong Liu, Haibo Zhou, Yang Liu, Qiang Tu, Liujie Huo, Fu Yan, Rolf Mueller, Youming Zhang, Xiaokun Xu
Summary: Engineering the biosynthetic pathways of complex natural products is a significant approach to obtain derivatives with improved properties. Here, we constructed a streamlined engineered biosynthesis system of myxobacterium-derived complex polyketide disorazol in a heterologous host. The inactivation of dehydratase domains led to the production of hydroxylated derivatives, while module deletion allowed the generation of an unnatural derivative with a truncated macrolactone ring. These disorazol derivatives showed different activities against human cancer cell lines, indicating a structure-activity relationship. The PKS engineering enables structural derivatization of disorazol, facilitating the in-depth engineered biosynthesis of polyketides.
ACS SYNTHETIC BIOLOGY
(2023)
Article
Biotechnology & Applied Microbiology
Judith Boldt, Laima Lukoseviciute, Chengzhang Fu, Matthias Steglich, Boyke Bunk, Vera Junker, Aileen Gollasch, Birte Trunkwalter, Kathrin I. Mohr, Michael Beckstette, Joachim Wink, Joerg Overmann, Rolf Mueller, Ulrich Nuebel
Summary: A better understanding of the genetic regulation of microbial compound biosynthesis can accelerate the discovery and production of new biologically active molecules. This study investigated the transcriptional dynamics of biosynthetic gene clusters (BGCs) in the myxobacterium Sorangium sp. So ce836, revealing that BGC transcription is associated with the production of natural compounds. The findings challenge the commonly held belief of preferential BGC expression under nutrient-limited conditions and highlight the need for genetic engineering tools to enhance compound yields from myxobacterial strains.
MICROBIAL BIOTECHNOLOGY
(2023)
Article
Chemistry, Multidisciplinary
Asfandyar Sikandar, Alexander Popoff, Ravindra P. Jumde, Attila Mandi, Amninder Kaur, Walid A. M. Elgaher, Lara Rosenberger, Stephan Huettel, Rolf Jansen, Maja Hunter, Jesko Koehnke, Anna K. H. Hirsch, Tibor Kurtan, Rolf Mueller
Summary: The absolute configuration of amidochelocardin was revised using a combination of XRD, NMR spectroscopy, experimental ECD spectra, and TDDFT-ECD calculations. Based on the biosynthetic engineering of chelocardin and the results of TDDFT-ECD calculations, it is proposed that chelocardin has the same absolute configuration. The evaluation of spectral data of two related analogues further supports this conclusion.
ANGEWANDTE CHEMIE-INTERNATIONAL EDITION
(2023)
Article
Biochemistry & Molecular Biology
Franziska Fries, Andreas Kany, Sari Rasheed, Anna Hirsch, Rolf Mueller, Jennifer Herrmann
Summary: A zebrafish embryo model was established to evaluate the in vivo efficacy of potential antimicrobials, providing a novel screening platform for antibiotic discovery. Consideration of the appropriate administration route based on the physicochemical properties of tested drugs was also provided.
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
(2023)
Article
Immunology
Carolin Blask, Juliane Schulze, Sarah Ruempel, Marie Suess, Matthias Grothe, Stefan Gross, Alexander Dressel, Rolf Mueller, Johanna Ruhnau, Antje Vogelgesang
Summary: By using acetyl-CoA-carboxylase inhibitors Soraphen A (SorA) and coenzyme A (CoA) ex vivo, the study aimed to decrease the release of proinflammatory cytokines and increase anti-inflammatory cytokine levels in PBMCs, indicating a potential application in future multiple sclerosis (MS) therapy. The analysis of cytokine production in PBMCs treated with SorA (10 or 50 nM) and CoA (600μM) showed immunomodulatory effects in MS patients, with a reduction in cytokine levels overall except for IL-2, IL-6, and IL-10.
JOURNAL OF NEUROIMMUNOLOGY
(2023)
Article
Biology
Sophia Gessner, Zela Alexandria-Mae Martin, Michael A. Reiche, Joana A. Santos, Ryan Dinkele, Atondaho Ramudzuli, Neeraj Dhar, Timothy J. de Wet, Saber Anoosheh, Dirk M. Lang, Jesse Aaron, Teng-Leong Chew, Jennifer Herrmann, Rolf Mueller, John D. McKinney, Roger Woodgate, Valerie Mizrahi, Ceslovas Venclovas, Meindert H. Lamers, Digby F. Warner
Summary: A study found that a DNA damage-inducible mutagenic gene cassette is involved in the emergence of drug resistance in Mycobacterium tuberculosis. The study also revealed the molecular composition and operation of the encoded 'mycobacterial mutasome'. These findings provide a new target for the development of adjunctive therapeutics to protect anti-TB drugs against emerging resistance.
