Article
Multidisciplinary Sciences
Paulina Fernandez-Soto, Joshua Casulli, Danilo Solano-Castro, Pablo Rodriguez-Fernandez, Thomas A. Jowitt, Mark A. Travis, Jennifer S. Cavet, Lydia Tabernero
Summary: SapM, a secreted virulence factor from Mycobacterium tuberculosis, is critical for pathogen survival and persistence inside the host. New potent inhibitors of SapM have been identified, which significantly reduce mycobacterial burden in infected human macrophages with selectivity. These findings provide a basis for developing new tuberculosis treatments and suggest the potential of SapM inhibitors for broad-spectrum microbial infection therapy.
SCIENTIFIC REPORTS
(2021)
Review
Microbiology
Kasi Viswanatharaju Ruddraraju, Devesh Aggarwal, Zhong-Yin Zhang
Summary: Tuberculosis is an airborne infectious disease caused by Mycobacterium tuberculosis, and the treatment of drug-resistant TB requires therapeutic agents with novel mechanisms. Antivirulence, focusing on bacterial virulence factors, is an alternative strategy for treating diseases. Recent advances in understanding the roles of mPTPA and mPTPB in the pathogenesis of TB have been made, along with the discovery of potent, selective, and well-characterized small molecule inhibitors for these proteins in the past decade.
Review
Chemistry, Medicinal
Caue Benito Scarim, Renan Lira de Farias, Adelino Vieira de Godoy Netto, Chung Man Chin, Jean Leandro dos Santos, Fernando Rogerio Pavan
Summary: Metal-based drugs serve as key pharmacophores in the development of new anti-TB drugs, with promising ligands like heterocyclic compounds, phosphines, schiff bases, thio and semicarbazones, aliphatic amines, cyclopalladated, cyanometallates. Metal-based complexes show potential for treating various diseases, including infectious diseases.
EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY
(2021)
Article
Multidisciplinary Sciences
Cameron C. Hanna, Anneliese S. Ashhurst, Diana Quan, Joshua W. C. Maxwell, Warwick J. Britton, Richard J. Payne
Summary: Researchers have developed a method for generating synthetic self-adjuvanted protein vaccines for tuberculosis and demonstrated their efficacy in providing significant protection in the lungs of mice. This flexible synthetic platform allows for incorporation of adjuvants to multiantigenic vaccines, offering a general approach for rapidly assessing vaccination strategies against a range of diseases, including novel pandemic pathogens such as SARS-CoV-2.
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
(2021)
Review
Biochemistry & Molecular Biology
Murtala A. Ejalonibu, Segun A. Ogundare, Ahmed A. Elrashedy, Morufat A. Ejalonibu, Monsurat M. Lawal, Ndumiso N. Mhlongo, Hezekiel M. Kumalo
Summary: Developing new antibiotics targeting resistant Mycobacterium tuberculosis is an appealing strategy to combat the global tuberculosis epidemic, with computational techniques playing a key role in drug design and discovery. Recent advancements in technology have enhanced the chances of drug development, offering hope in the fight against tuberculosis resistance.
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
(2021)
Article
Biochemistry & Molecular Biology
Wataru Asano, Kenji Yamanaka, Yasunori Ohara, Toru Uhara, Satoki Doi, Takuya Orita, Tomoko Iwanaga, Tsuyoshi Adachi, Shingo Fujioka, Tatsuo Akaki, Kazutaka Ikegashira, Yoshiji Hantani
Summary: Tyrosine phosphorylation is a vital post-translational modification that regulates various biological events and is linked to numerous diseases. Vascular endothelial protein tyrosine phosphatase (VE-PTP) is an important target for diseases like cancer and atherosclerosis. In this study, a new VE-PTP inhibitor, Cpd-2, was discovered through fragment-based screening and biophysical techniques. Cpd-2 is the first weakly acidic and highly selective VE-PTP inhibitor, showing potential for the development of bioavailable inhibitors.
Review
Biochemistry & Molecular Biology
Alexander D. H. Kingdon, Luke J. Alderwick
Summary: Mycobacterium tuberculosis is the causative agent of TB and drug resistance is a growing issue, necessitating the need for novel antimycobacterial drugs. Increased knowledge of gene essentiality and compound databases can aid in the discovery of new drug compounds. The increasing number of protein structures allows for investigation of novel targets.
COMPUTATIONAL AND STRUCTURAL BIOTECHNOLOGY JOURNAL
(2021)
Article
Biotechnology & Applied Microbiology
Fangxue Ma, Hong Zhou, Zhiqiang Yang, Chao Wang, Yanan An, Lihui Ni, Mingyuan Liu, Yang Wang, Lu Yu
Summary: This study developed a modified in vitro M. tuberculosis biofilm model with shorter culture time and used Illumina RNA-seq technology to identify the global gene expression profile of M. tuberculosis biofilms. The results showed that genes involved in various metabolic pathways are differentially expressed in biofilm cells compared to planktonic cells, providing insights into potential target genes and strategies for M. tuberculosis biofilm inhibition.
APPLIED MICROBIOLOGY AND BIOTECHNOLOGY
(2021)
Article
Chemistry, Analytical
Honghong Wang, Shuhui Wang, Hui Wang, Yuanwen Liang, Zhengping Li
Summary: Fusion genes, as causative oncogenes and drug targets, play critical roles in tumor development and treatment. A specific and sensitive method for quantifying fusion transcripts was proposed, which uses stem-loop primers to track fusion junctions and initiates reverse transcript loop-mediated isothermal amplification (LAMP). The method achieved high sensitivity and a wide linear dynamic range, simplifying the detection process and effectively eliminating false-positive results.
Review
Immunology
Amala Bhagwat, Aditi Deshpande, Tanya Parish
Summary: This article discusses various approaches and strategies to address drug resistance in tuberculosis, including developing new drugs or drug combinations, improving the efficacy of existing drugs, and understanding the importance of resistance mechanisms and cross-resistance.
FRONTIERS IN CELLULAR AND INFECTION MICROBIOLOGY
(2022)
Review
Biochemistry & Molecular Biology
Uday S. Ganapathy, Thomas Dick
Summary: Mycobacterium abscessus lung disease is highly drug-resistant and lacks reliable treatment options. Prioritizing the screening of advanced Tuberculosis (TB)-active compounds can effectively accelerate the discovery of anti-M. abscessus drugs, increasing the success rate of drug development.
Article
Chemistry, Analytical
Elodie Barbier, Theo Fouchet, Alain Hartmann, Emmanuelle Cambau, Faiza Mougari, Clement Dubois, Maurice Lubetzki, Murielle Rochelet
Summary: An electrochemical assay was developed for the qualitative detection of Mycobacterium tuberculosis by detecting the enzymatic activity of the Ag85 biomarker. The method showed a specificity of 78% and a sensitivity of 89%, making it a promising tool for screening patients for TB.
Article
Biochemistry & Molecular Biology
Rahul Balasaheb Aher, Dhiman Sarkar
Summary: The newly approved drug Pretomanid has shown promising antitubercular activity against both replicating and non-replicating forms of Mycobacterium tuberculosis, based on experimental data of its derivatives.
JOURNAL OF BIOMOLECULAR STRUCTURE & DYNAMICS
(2021)
Article
Respiratory System
Georgina R. Nyawo, Charissa C. Naidoo, Benjamin Wu, Imran Sulaiman, Jose C. Clemente, Yonghua Li, Stephanie Minnies, Byron W. P. Reeve, Suventha Moodley, Cornelia Rautenbach, Colleen Wright, Shivani Singh, Andrew Whitelaw, Pawel Schubert, Robin Warren, Leopoldo Segal, Grant Theron
Summary: This study investigated the lymph node microbiome in tuberculosis lymphadenitis (TBL) patients and found that the microbiome in TBL lymph nodes is diverse. Different microbial communities are associated with different clinical features and immunomodulatory potentials. These findings lay the groundwork for studying the role of the microbiome in lymphatic TB.
Article
Multidisciplinary Sciences
Su-Young Kim, Dae Hun Kim, Seong Mi Moon, Ju Yeun Song, Hee Jae Huh, Nam Yong Lee, Sung Jae Shin, Won-Jung Koh, Byung Woo Jhun
Summary: This study evaluated the association between rrs mutations and amikacin resistance in clinical isolates of NTM in NTM-PD patients. The findings showed a higher prevalence of rrs mutations in high-level amikacin-resistant MAC isolates compared to low-level isolates, while all amikacin-resistant M. abscessus isolates had rrs mutations. These results emphasize the significance of phenotypic and genotypic susceptibility testing in managing MAC and M. abscessus-PD.
SCIENTIFIC REPORTS
(2021)
Article
Biochemistry & Molecular Biology
Francesco Brunori, Deepak Kumar Padhi, Israel Alshanski, Joanna Freyse, Jan-Niklas Duerig, Anja Penk, Luigi Vaccaro, Mattan Hurevich, Joerg Rademann, Shlomo Yitzchaik
Summary: We evaluated the effect of hyaluronan sulfation degree and Fe3+ on interleukin-8 binding by electrochemical impedance spectroscopy and surface characterizations. Our results demonstrate a synergistic effect of sulfation degree and metal ion interactions in tuning the electrochemical response of glycated surfaces to the cytokine.
Review
Chemistry, Organic
Ahsanullah, Abbas Hassan, Farzana L. Ansari, Joerg Rademann
Summary: The modification of native peptides to peptidomimetics is an important goal in medicinal chemistry, and using Meldrum's acid and phosphorus and sulfur ylides for peptide-compatible C-acylation is an effective method to achieve this goal.
SYNTHESIS-STUTTGART
(2022)
Article
Chemistry, Multidisciplinary
Matteo Accorsi, Markus Tiemann, Leon Wehrhan, Lauren M. Finn, Ruben Cruz, Max Rautenberg, Franziska Emmerling, Joachim Heberle, Bettina G. Keller, Joerg Rademann
Summary: This study reports the discovery and investigation of pentafluorophosphato amino acids as novel phosphotyrosine biomimetics. Experimental and computational methods were used to demonstrate that these novel biomimetics have significantly enhanced binding affinity to the protein tyrosine phosphatase PTP1B, suggesting their potential value in drug molecule development.
ANGEWANDTE CHEMIE-INTERNATIONAL EDITION
(2022)
Article
Genetics & Heredity
Fatemeh Ghorbani, Mohamed Z. Alimohamed, Juliana F. Vilacha, Krista K. Van Dijk, Jelkje De Boer-Bergsma, Michiel R. Fokkens, Henny Lemmink, Rolf H. Sijmons, Birgit Sikkema-Raddatz, Matthew R. Groves, Corien C. Verschuuren-Bemelmans, Dineke S. Verbeek, Cleo C. Van Diemen, Helga Westers
Summary: Spinocerebellar ataxia (SCA) is a group of neurodegenerative disorders with autosomal dominant inheritance. Genetic testing plays an important role in the diagnosis, prognosis and risk assessment for patients and their families. This study addressed the challenge of prioritizing variants with unknown significance (VUSes) for follow-up, and successfully increased the molecular diagnostic yield by 1.1% through reclassification of VUSes.
FRONTIERS IN GENETICS
(2022)
Article
Chemistry, Multidisciplinary
Markus Tiemann, Eric Nawrotzky, Peter Schmieder, Leon Wehrhan, Silke Bergemann, Vera Martos, Wei Song, Christoph Arkona, Bettina G. Keller, Joerg Rademann
Summary: Formylglycine is investigated as a molecular probe for the sensitive detection of fragments binding to a specific protein site. The formylglycine probe identified low-affinity fragments with high spatial resolution, and the best fragment hit was converted into a cellularly active, nanomolar inhibitor of the protein tyrosine phosphatase SHP2.
CHEMISTRY-A EUROPEAN JOURNAL
(2022)
Article
Chemistry, Medicinal
Eman Abdelraheem, Max Lubberink, Wenja Wang, Jingyao Li, Atilio Reyes Romero, Robin van der Straat, Xiaochen Du, Matthew Groves, Alexander Doemling
Summary: IL-17a is a major inflammation target, with the emergence of small-molecule IL-17a antagonists as a hot topic. Research has found that all described IL-17a modifiers belong to the same pharmacophore model.
ACS MEDICINAL CHEMISTRY LETTERS
(2022)
Article
Multidisciplinary Sciences
Zayana M. Al-Dahmani, Xiaogang Li, Lucas M. Wiggenhauser, Hannes Ott, Paul D. Kruithof, Sergey Lunev, Fernando A. Batista, Yang Luo, Amalia M. Dolga, Nicholas M. Morton, Matthew R. Groves, Jens Kroll, Harry van Goor
Summary: Thiosulfate sulfurtransferase (TST) is a genetic predictor of resistance to obesity-related type 2 diabetes, and its activation might be a promising option for therapeutic intervention in diabetes and its complications.
SCIENTIFIC REPORTS
(2022)
Article
Chemistry, Multidisciplinary
Chao Wang, Bidong Zhang, Arne Kruger, Xiaochen Du, Lidia Visser, Alexander S. S. Domling, Carsten Wrenger, Matthew R. Groves
Summary: This study describes a series of small-molecule inhibitors targeting P. falciparum ATC with low nanomolar binding affinities, selectively binding to a previously unreported allosteric pocket, inhibiting ATC activation.
JOURNAL OF THE AMERICAN CHEMICAL SOCIETY
(2022)
Article
Biochemistry & Molecular Biology
Nika Sokolova, Lili Zhang, Sadaf Deravi, Rick Oerlemans, Matthew R. Groves, Kristina Haslinger
Summary: Oxygen-directed methylation is a common tailoring reaction in natural product pathways catalyzed by O-methyltransferases (OMTs). Two bacterial OMTs from Desulforomonas acetoxidans and Streptomyces avermitilis were characterized for their enzymatic properties and substrate scope, and their crystal structures were determined. Both OMTs methylated a wide range of catechol-like substrates, including flavonoids, coumarins, hydroxybenzoic acids, and their respective aldehydes, an anthraquinone and an indole. This study expands knowledge on the substrate preference and structural diversity of bacterial catechol OMTs and opens up possibilities for their use in (combinatorial) pathway engineering.
Article
Chemistry, Medicinal
Xiaochen Du, Vidhisha Sonawane, Bidong Zhang, Chao Wang, Bram de Ruijter, Alexander S. S. Domling, Norbert Reiling, Matthew R. Groves
Summary: Aspartate transcarbamoylase (ATCase) is a target for suppressing cell proliferation in E. coli, human cells and the malarial parasite. This study aimed to test if a library of ATCase inhibitors developed for malarial ATCase (PfATCase) also inhibit the tubercular ATCase and show similar effects on cellular proliferation. Screening of 70 compounds revealed 10 inhibitors with single-digit micromolar inhibition in vitro, and the most promising compound showed a MIC90 of 4 μM against M. tuberculosis cell growth. In silico docking experiments explained the species selectivity observed for this compound series.
Article
Biochemical Research Methods
Oladapo Olaleye, Christian Graf, Baubek Spanov, Natalia Govorukhina, Matthew R. Groves, Nico C. van de Merbel, Rainer Bischoff
Summary: Hydrogen-deuterium exchange mass spectrometry (HDX-MS) is a method to study the solvent accessibility and conformational dynamics of proteins. In this study, HDX-MS was used to determine the binding sites of Affimer reagents on monoclonal antibodies trastuzumab and pertuzumab. The results showed that the affimer binding led to significant protection in the Fab region of the antibodies. The binding sites of the affimer reagents were mainly located in the CDR2 of the heavy chain of the antibodies, as revealed by bottom-up HDX-MS experiments.
JOURNAL OF THE AMERICAN SOCIETY FOR MASS SPECTROMETRY
(2023)
Article
Crystallography
Victor Oliveira Gawriljuk, Rick Oerlemans, Robin M. Gierse, Riya Jotwani, Anna K. H. Hirsch, Matthew R. Groves
Summary: The development of new antibiotics is stagnant, highlighting the need for drugs with novel modes of action to combat antibiotic resistance. A study focuses on 1-deoxy-D-xylulose 5-phosphate synthase (DXPS), the rate-limiting enzyme in the methylerythritol phosphate pathway used by bacteria to synthesize important precursors. The crystal structure of M. tuberculosis DXPS in complex with the inhibitor butylacetylphosphonate (BAP) reveals its binding mode and provides insights for enhancing the activity of alkylacetylphosphonates (alkylAPs) against M. tuberculosis.
Review
Oncology
Fenneke Zwierenga, Bianca A. M. H. van Veggel, Anke Van den Berg, Harry J. M. Groen, Lili Zhang, Matthew R. Groves, K. Kok, E. F. Smit, T. Jeroen N. Hiltermann, Adrianus J. de Langen, Anthonie J. Van der Wekken
Summary: This article provides a comprehensive assessment of drug sensitivity in vitro and in clinical settings for EGFRex20+ mutations in NSCLC. The activating A763_Y764insFQEA mutation shows better tumor response compared to mutations in other regions, suggesting the need for different treatment approaches. Classification beyond exon-based categories is necessary due to marked differences in treatment responses among EGFRex20+ mutations.
CANCER TREATMENT REVIEWS
(2023)
Article
Biochemistry & Molecular Biology
Zeyana M. Al-Dahmani, Mojgan Hadian, Angel J. Ruiz-Moreno, Sabogal-Guaqueta Angelica Maria, Fernando A. Batista, Ran Zhang, Yang Luo, Afsaneh Sadremomtaz, Robin van der Straat, Mette Spoor, Amalia M. Dolga, Frank J. Dekker, S. S. Alexander Domling, Harry van Goor, Matthew R. Groves
Summary: A small molecule activator of human TST, identified through screening, increases TST activity and may have therapeutic benefits for diabetes and obesity. Two distinct isomers and an allosteric mode of activation are required for full activation. Molecular docking and dynamics suggest an allosteric site for the activator's binding, and increased TST activity enhances mitochondrial respiration.
Article
Biochemistry & Molecular Biology
Yang Luo, Laurent Chatre, Shaden Melhem, Zayana M. Al-Dahmani, Natalie Z. M. Homer, Anneke Miedema, Leo E. Deelman, Matthew R. Groves, Martin Feelisch, Nicholas M. Morton, Amalia Dolga, Harry van Goor
Summary: This study reveals that TST deficiency leads to disturbances in the reactive species interactome in the brain cortex, resulting in altered ROS and RSS (specifically, polysulfide) generation, as well as mitochondrial OXPHOS remodeling. These changes are associated with abnormal Nrf2-Keap1 expression and thiol-dependent antioxidant function. Tst-/- mice exhibit lower antioxidant capacity compared to wildtype controls when challenged with the redox-active herbicide paraquat.
