Article
Microbiology
Miriam Garcia-Lopez, Diego Megias, Maria-Jose Ferrandiz, Adela G. de la Campa
Summary: Two enzymes, gyrase and topoisomerase I, play important roles in maintaining supercoiling in Streptococcus pneumoniae. The ratio of these enzymes affects supercoiling and cell viability, suggesting a potential mechanism for the action of topoisomerase-targeting antibiotics.
FRONTIERS IN MICROBIOLOGY
(2023)
Article
Biochemistry & Molecular Biology
Paul Villain, Ryan Catchpole, Patrick Forterre, Jacques Oberto, Violette da Cunha, Tamara Basta
Summary: This study reveals the evolutionary history of DNA gyrase in Archaea using phylogenomic approaches and sequence datasets. The results suggest that DNA gyrase was introduced into Euryarchaeal group II through horizontal gene transfer from bacterial ancestors. Furthermore, DNA gyrase has spread to other Archaea lineages through rare horizontal gene transfers. The study also shows the co-evolution of DNA gyrase and Topoisomerase VI in Archaea.
MOLECULAR BIOLOGY AND EVOLUTION
(2022)
Article
Biochemistry & Molecular Biology
Maiwenn Pineau, Shiny B. Martis, Raphael Forquet, Jessica Baude, Camille Villard, Lucie Grand, Florence Popowycz, Laurent Soulere, Florence Hommais, William Nasser, Sylvie Reverchon, Sam Meyer
Summary: DNA supercoiling is a crucial mechanism in bacterial chromosome compaction, which is regulated by specific topoisomerases, physiological conditions, and genomic context. The altered supercoiling level leads to changes in global gene expression in bacteria.
NUCLEIC ACIDS RESEARCH
(2022)
Article
Biochemistry & Molecular Biology
Katja E. Menger, James Chapman, Hector Diaz-Maldonado, Mushtaq M. Khazeem, Dasha Deen, Direnis Erdinc, John W. Casement, Valeria Di Leo, Angela Pyle, Alejandro Rodriguez-Luis, Ian G. Cowell, Maria Falkenberg, Caroline A. Austin, Thomas J. Nicholls
Summary: The activity of two topoisomerases, TOP3A and TOP1MT, is essential for the maintenance and expression of human mitochondrial DNA. Both topoisomerases contribute to mtDNA replication, with TOP1MT being stimulated by mtSSB. Loss of these topoisomerases leads to dysregulation of mitochondrial gene expression.
NUCLEIC ACIDS RESEARCH
(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
Biochemistry & Molecular Biology
Antonio A. A. de Vasconcelos Junior, Jose M. Tirado-Velez, Antonio J. Martin-Galiano, Diego Megias, Maria-Jose Ferrandiz, Pablo Hernandez, Monica Amblar, Adela G. de la Campa
Summary: In this study, a new topoisomerase I regulator protein (StaR) was characterized in Streptococcus pneumoniae. It was found that StaR directly affects novobiocin susceptibility and needs to be maintained within a narrow range.
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
(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
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
Biochemistry & Molecular Biology
Larissa Kever, Max Hunnefeld, Jannis Brehm, Ralf Heermann, Julia Frunzke
Summary: Bacteriophages can be a powerful source for identifying novel antimicrobial proteins by targeting key regulatory hubs of their host. The Gip protein, encoded by CGP3 prophage, was found to interact directly with DNA gyrase subunit A and specifically inhibit the DNA gyrase of Corynebacterium glutamicum, resulting in growth defects and induction of the SOS response. The overexpression of Gip also led to the induction of the cryptic CGP3 prophage, likely caused by topological alterations.
MOLECULAR MICROBIOLOGY
(2021)
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
John G. G. Cumming, Lukas Kreis, Holger Kuehne, Roger Wermuth, Maarten Vercruysse, Christian Kramer, Markus G. G. Rudolph, Zhiheng Xu
Summary: Novel bacterial topoisomerase inhibitors (NBTIs) have been discovered to target clinically validated bacterial type II topoisomerases and effectively combat multidrug-resistant Gram-negative bacteria. The discovery of a series of NBTIs with a novel indane DNA binding moiety, as well as their interaction with Staphylococcus aureus DNA gyrase-DNA, has been reported. The lead compound 18c shows potent broad-spectrum activity against multidrug-resistant Gram-negative bacteria.
ACS MEDICINAL CHEMISTRY LETTERS
(2023)
Article
Biochemistry & Molecular Biology
Heba A. Hofny, Mamdouh F. A. Mohamed, Hesham A. M. Gomaa, Salah A. Abdel-Aziz, Bahaa G. M. Youssif, Nawal A. El-koussi, Ahmed S. Aboraia
Summary: New quinoline-1,3,4-oxadiazole and quinoline-1,2,4-triazole hybrids were developed and tested for their activity against DNA gyrase and topoisomerase IV. Some compounds showed strong antibacterial activity without cytotoxic effects, and molecular docking analysis was performed to investigate their binding mode and interactions with the enzymes.
BIOORGANIC CHEMISTRY
(2021)
Article
Biochemistry & Molecular Biology
Piotr Roszkowski, Jolanta Szymanska-Majchrzak, Michal Kolinski, Sebastian Kmiecik, Malgorzata Wrzosek, Marta Struga, Daniel Szulczyk
Summary: Eleven novel imide-tetrazoles were synthesized and screened for antimicrobial activity. Compounds 1-3 showed the most promising results with minimal inhibitory concentration values within the range of 0.8-3.2 μg/mL. These compounds exhibited higher activity than the reference drug in some cases. They also inhibited the growth of clinical Staphylococci panels with MIC values of 0.8 μg/mL. Further studies on the binding modes of these compounds suggest their potential as novel antimicrobial drug candidates.
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
(2022)
Article
Immunology
Olivier Papapietro, Sergey Nejentsev
Summary: TOP2B plays a crucial role in transcription regulation and maintaining genome organization by unwinding DNA structures. Deficiency of TOP2B may lead to developmental defects in B-cell progenitors.
FRONTIERS IN IMMUNOLOGY
(2022)
Article
Chemistry, Medicinal
Heba S. A. El-Zahabi, Eman S. Nossier, Safya M. Mousa, Heba Hassan, Al Shimaa G. Shalaby, Reem K. Arafa
Summary: This study synthesized a series of new benzocaine derivatives, with thiazolidines 6 and 7b showing higher antibacterial and anticancer activity. These compounds were also found to have high potency as inhibitors towards their biological targets, making them potential lead compounds for the design of more potent antibacterial and anticancer agents.
ARCHIV DER PHARMAZIE
(2022)
Article
Microbiology
Paloma Soler-Arnedo, Claudia Sala, Ming Zhang, Stewart T. Cole, Jeremie Piton
JOURNAL OF BACTERIOLOGY
(2020)
Article
Microbiology
E. D. Pieterman, M. J. Sarink, C. Sala, S. T. Cole, J. E. M. de Steenwinkel, H. I. Bax
ANTIMICROBIAL AGENTS AND CHEMOTHERAPY
(2020)
Article
Biochemistry & Molecular Biology
Oskar Franch, Camino Gutierrez-Corbo, Barbara Dominguez-Asenjo, Thomas Boesen, Pia Bomholt Jensen, Lene N. Nejsum, Josephine Geertsen Keller, Simon Pagaard Nielsen, Prakruti R. Singh, Rajiv Kumar Jha, Valakunja Nagaraja, Rafael Balana-Fouce, Yi-Ping Ho, Rosa Maria Reguera, Birgitta Ruth Knudsen
NUCLEIC ACIDS RESEARCH
(2020)
Review
Chemistry, Multidisciplinary
Raphael Gries, Claudia Sala, Jan Rybniker
APPLIED SCIENCES-BASEL
(2020)
Editorial Material
Biochemistry & Molecular Biology
Simone Pecetta, Mariagrazia Pizza, Claudia Sala, Emanuele Andreano, Piero Pileri, Marco Troisi, Elisa Pantano, Noemi Manganaro, Rino Rappuoli
CELL DEATH AND DIFFERENTIATION
(2021)
Article
Microbiology
Thyago Leal-Calvo, Charlotte Avanzi, Mayara Abud Mendes, Andrej Benjak, Philippe Busso, Roberta Olmo Pinheiro, Euzenir Nunes Sarno, Stewart Thomas Cole, Milton Ozorio Moraes
Summary: Transcriptional profiling is a powerful tool for investigating human diseases. This study used RNA-Seq to compare skin lesion transcriptomes in leprosy patients, identifying five genes capable of accurately distinguishing different types of leprosy. The research concluded that paucibacillary leprosy is characterized by epithelioid transformation and granuloma formation with an exacerbated cellular immune response, while multibacillary leprosy features epithelial-mesenchymal transition with phagocytic and lipid biogenesis patterns in the skin.
Article
Biochemistry & Molecular Biology
Kushi Anand, Ashutosh Tripathi, Kaustubh Shukla, Nitish Malhotra, Anil Kumar Jamithireddy, Rajiv Kumar Jha, Susmit Narayan Chaudhury, Raju S. Rajmani, Arati Ramesh, Valakunja Nagaraja, Balasubramanian Gopal, Ganesh Nagaraju, Aswin Sai Narain Seshayee, Amit Singh
Summary: The study reveals that the transcription factor SufR senses NO and promotes the persistence of Mycobacterium tuberculosis by mobilizing the Fe-S cluster biogenesis system. NO directly damages Fe-S clusters, resulting in the inability of Mtb to recover from a non-growing state, ultimately leading to a persistence defect in immune-activated host cells and murine lungs.
Article
Microbiology
Ze Long Lim, Kylee Drever, Neeraj Dhar, Stewart T. Cole, Jeffrey M. Chen
Summary: The ESX-1 system plays a crucial role in the virulence of Mycoabcterium tuberculosis. This study reveals that EspK is essential for the secretion of EsxA and EspB in M. tuberculosis and prevents premature assembly of EspB into nonsecretable structures.
JOURNAL OF BACTERIOLOGY
(2022)
Review
Cell Biology
Rajiv Kumar Jha, David Levens, Fedor Kouzine
Summary: This article provides an overview of the current understanding of DNA and chromatin mechanics in gene expression, highlighting the importance of mechanical determinants imposed by DNA transactions on the three-dimensional organization of the genome.
Review
Biochemistry & Molecular Biology
Pardis Mokhtary, Zeinab Pourhashem, Akram Abouei Mehrizi, Claudia Sala, Rino Rappuoli
Summary: Monoclonal antibodies are a revolutionary class of medications that can bind specific targets and receptors to combat various diseases. New technologies, such as gene delivery, have been developed to improve their efficacy and delivery routes, enabling them to be used in the treatment of viral infections and outbreaks.
Review
Biochemistry & Molecular Biology
Fabiola Vacca, Claudia Sala, Rino Rappuoli
Summary: Monoclonal antibody therapy has significant potential in the pharmaceutical field, particularly in combating antibiotic resistance in bacteria. However, there is a need for further improvement in the efficacy of antibacterial monoclonal antibodies.
Article
Chemistry, Medicinal
Aiste Dobrovolskaite, Holly Moots, Mukund P. Tantak, Kunal Shah, Jenna Thomas, Sharifa Dinara, Chelsea Massaro, Paul M. Hershberger, Patrick R. Maloney, Satyamaheshwar Peddibhotla, Eliot Sugarman, Sally Litherland, Juan Pablo Arnoletti, Rajiv Kumar Jha, David Levens, Otto Phanstiel
Summary: This study discovered a compound that potentiates the ODC inhibitor DFMO and identified FUBP1 as its target. The compound works synergistically with DFMO to limit cell growth and affects the expression levels of FUBP1-associated genes and intracellular polyamines.
JOURNAL OF MEDICINAL CHEMISTRY
(2022)
Article
Multidisciplinary Sciences
Brian A. Lewis, Subhendu Kumar Das, Rajiv Kumar Jha, David Levens
Summary: This study reveals the existence of dense and transcriptionally active biomolecular condensates (BMCs) in the nucleus, which can represent the physiological nuclear environment. This finding is crucial for further understanding transcriptional regulation mechanisms.
Article
Biochemistry & Molecular Biology
Subhendu K. Das, Vladislav Kuzin, Donald P. Cameron, Suzanne Sanford, Rajiv Kumar Jha, Zuqin Nie, Marta Trullols Rosello, Ronald Holewinski, Thorkell Andresson, Jan Wisniewski, Toyoaki Natsume, David H. Price, Brian A. Lewis, Fedor Kouzine, David Levens, Laura Baranello
Summary: MYC is directly associated with topoisomerase 1 (TOP1) and TOP2, and it stimulates their activities, leading to increased levels of these enzymes on DNA and promotion of genome function.