Review
Cell Biology
Zilu Wang, Jianping Xie
Summary: Phosphorylation plays a crucial role in tuberculosis research by revealing the interaction between the pathogen and the host, leading to the development of new measures for prevention and treatment.
CELLULAR SIGNALLING
(2022)
Article
Chemistry, Medicinal
Melina Chebaiki, Evelyne Delfourne, Rasoul Tamhaev, Saida Danoun, Frederic Rodriguez, Pascal Hoffmann, Emeline Grosjean, Fernanda Goncalves, Joelle Azema-Despeyroux, Adrian Pal, Jana Kordulakova, Nadege Preuilh, Sebastien Britton, Patricia Constant, Hedia Marrakchi, Laurent Maveyraud, Lionel Mourey, Christian Lherbet
Summary: Tuberculosis caused by Mycobacterium tuberculosis affects 10 million people annually, and the emergence of drug-resistant strains poses a growing threat. With only three new drugs approved for TB treatment in the past 60 years, there is an urgent need for new chemotherapeutic agents. This study focuses on the development of direct inhibitors of InhA, a key enzyme involved in TB survival, and demonstrates their potential as effective and less toxic drugs.
EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY
(2023)
Article
Biochemistry & Molecular Biology
Abdalrahman Khalifa, Amira Khalil, Marwa M. Abdel-Aziz, Amgad Albohy, Samy Mohamady
Summary: Tuberculosis is a global problem due to drug-resistant strains, and this study focuses on developing new antitubercular drugs by inhibiting a specific enzyme. The synthesized isatin derivatives, especially compound 4l, have shown promising potential in treating TB by inhibiting the target enzyme. Molecular docking and dynamics studies provide insights into the mechanism of action and stability of the compound. This research sets the foundation for the design and synthesis of novel antitubercular drugs.
BIOORGANIC CHEMISTRY
(2023)
Article
Microbiology
Matt D. Johansen, Shalini, Sumit Kumar, Clement Raynaud, Diana H. Quan, Warwick J. Britton, Philip M. Hansbro, Vipan Kumar, Laurent Kremer
Summary: The designed and synthesized isatin-isoniazid hybrids exhibit high antimycobacterial activity against tuberculosis, well-tolerated with good selectivity in kidney cells, and are effective in infected macrophages, indicating their potential as promising antitubercular compounds for further evaluation in preclinical settings.
ANTIMICROBIAL AGENTS AND CHEMOTHERAPY
(2021)
Article
Cell Biology
Ming-Chih Yu, Ching-Sheng Hung, Chun-Kai Huang, Cheng-Hui Wang, Yu-Chih Liang, Jung-Chun Lin
Summary: In this study, whole-genome sequencing of clinical MTB clones was carried out using a long-read sequencing approach, identifying nucleotide variants associated with INH resistance. The presence of high-INH resistance signature was accurately estimated through the consistency of genotypic profiles, susceptibility test, and minimal inhibitory concentration results.
JOURNAL OF BIOMEDICAL SCIENCE
(2021)
Article
Biochemical Research Methods
Qing Ye, Xin Chai, Dejun Jiang, Liu Yang, Chao Shen, Xujun Zhang, Dan Li, Dongsheng Cao, Tingjun Hou
Summary: This study developed classification models using machine learning algorithms to distinguish Mtb inhibitors from noninhibitors, with the XGBoost model showing the best prediction performance. Two consensus strategies were employed to integrate predictions from multiple models, resulting in the best predictions. The association between important descriptors and bioactivities of molecules was interpreted, and an online tool called ChemTB was developed for detecting potential Mtb inhibitors.
BRIEFINGS IN BIOINFORMATICS
(2021)
Article
Microbiology
Uday S. Ganapathy, Ruben Gonzalez Del Rio, Monica Cacho-Izquierdo, Fatima Ortega, Joel Lelievre, David Barros-Aguirre, Wassihun Wedajo Aragaw, Matthew D. Zimmerman, Marissa Lindman, Veronique Dartois, Martin Gengenbacher, Thomas Dick
Summary: Fluoroquinolones are effective against tuberculosis but have limited clinical use for nontuberculous mycobacteria infections due to drug resistance. Researchers tested alternative DNA gyrase inhibitors and found that the MGI EC/11716 not only works against mycobacterium tuberculosis, but also M. abscessus and M. avium. The study showed that EC/11716 is bactericidal against M. abscessus, effective against drug-tolerant biofilms, and successful in a mouse model of M. abscessus lung infection.
ANTIMICROBIAL AGENTS AND CHEMOTHERAPY
(2021)
Article
Infectious Diseases
Sacha J. Pidot, Jessica L. Porter, Troy Lister, Timothy P. Stinear
Summary: Nontuberculosis mycobacterial (NTM) infections are on the rise globally, with limited treatment options available. However, the development of new antimycobacterial drugs shows promise in addressing this issue. The novel antibiotic SPR719 has shown activity against NTM species, with a MIC range of 0.125-4 μg/ml, comparable to commonly used antimycobacterial antibiotics such as rifampicin and clarithromycin. Further evaluation of SPR720 for NTM infection treatment is warranted.
PLOS NEGLECTED TROPICAL DISEASES
(2021)
Article
Biochemistry & Molecular Biology
L. S. Dhivya, Sabarathinam Sarvesh, Ankul S. Singh
Summary: Tuberculosis is a serious infectious disease caused by Mycobacterium tuberculosis. The study discovered potentially effective anti-TB therapies in the form of certain Chalcones compounds, which are believed to be due to their specific structures.
JOURNAL OF BIOMOLECULAR STRUCTURE & DYNAMICS
(2023)
Article
Biochemistry & Molecular Biology
Mohamed H. Younis, Eman R. Mohammed, Abdalla R. Mohamed, Marwa M. Abdel-Aziz, Hanan H. Georgey, Nagwa M. Abdel Gawad
Summary: This study focuses on the design and synthesis of new compounds to evaluate their activity against Mycobacterium tuberculosis and bronchitis-causing bacteria. Several compounds showed promising results, particularly compound 3 and 7c, which demonstrated strong antibacterial and inhibitory activity against Mycobacterium tuberculosis.
BIOORGANIC CHEMISTRY
(2022)
Article
Chemistry, Medicinal
Markus Lang, Uday S. Ganapathy, Lea Mann, Rana Abdelaziz, Rudiger W. Seidel, Richard Goddard, Ilaria Sequenzia, Sophie Hoenke, Philipp Schulze, Wassihun Wedajo Aragaw, Rene Csuk, Thomas Dick, Adrian Richter
Summary: This study describes the derivatization of MMV688845 by introducing a thiomorpholine moiety, and the preparation of the corresponding sulfones and sulfoxides. The molecular structures of three analogs are confirmed by X-ray crystallography, and the essential R configuration is proven to be conserved during synthesis. All analogs are characterized in a MIC assay against various mycobacteria, and the sulfone derivatives exhibit lower MIC90 values and higher aqueous solubility compared to the hit compound. The most potent derivatives possess bactericidal activity against Mycobacterium abscessus without being cytotoxic to mammalian cell lines.
JOURNAL OF MEDICINAL CHEMISTRY
(2023)
Article
Chemistry, Medicinal
Kyle D. Farrell, Yamin Gao, Deborah A. Hughes, Robin Henches, Zhengchao Tu, Michael Perkins, Tianyu Zhang, Craig L. Francis
Summary: A series of 3-methoxy-2-phenylimidazo[1,2-b]pyridazine derivatives were found to be highly active against autoluminescent Mycobacterium tuberculosis (Mtb) and Mycobacterium marinum (Mm) in vitro. SAR analysis revealed that the most active compounds exhibited in vitro MIC90 values generally around 0.63-1.26 μM against Mtb and Mm, but were inactive against Mtb in vivo (mice) due to very short metabolic half-lives when incubated with mouse liver microsomes, possibly through oxidative cleavage of the imidazole moiety.
EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY
(2023)
Article
Biochemistry & Molecular Biology
Muhammad Hassam, Kanwal Khan, Khurshid Jalal, Muhammad Tariq, Syed Tarique Moin, Reaz Uddin
Summary: In this study, the Pantothenate synthetase (PS) drug target was analyzed using docking and virtual screening approaches. Eight potent inhibitors of PS were identified. The binding energy results were validated through Enrichment Factor analysis. These decoy compounds, which exhibited properties similar to the active compounds, are suggested as potential candidates for treating Mycobacterium tuberculosis infection.
JOURNAL OF BIOMOLECULAR STRUCTURE & DYNAMICS
(2023)
Article
Infectious Diseases
Delia Mercedes Bianco, Flavio De Maio, Giulia Santarelli, Ivana Palucci, Alessandro Salustri, Giada Bianchetti, Giuseppe Maulucci, Franco Citterio, Maurizio Sanguinetti, Enrica Tamburrini, Michela Sali, Giovanni Delogu
Summary: Despite being investigated as a host-directed therapy in treating tuberculosis, Everolimus showed no direct or indirect activity against Mycobacterium tuberculosis (Mtb). Even in an immunosuppressed patient, Everolimus did not affect the viability of Mtb and had minimal impact in host cells during infection. This case emphasizes the importance of careful drug repurposing and pre-clinical experimental studies.
Article
Microbiology
Francoise Roquet-Baneres, Mattheo Alcaraz, Claire Hamela, Jan Abendroth, Thomas E. Edwards, Laurent Kremer
Summary: Researchers have discovered that a compound called NITD-916 displays potent antimicrobial activity against M. fortuitum both in vitro and in vivo. This compound inhibits the growth of M. fortuitum by targeting InhA(MFO) and shows promising effectiveness against drug resistance. This study suggests that NITD-916 could be a potential drug for the treatment of M. fortuitum pulmonary diseases.
ANTIMICROBIAL AGENTS AND CHEMOTHERAPY
(2023)
Article
Biochemistry & Molecular Biology
Christopher E. Evans, Yuanyuan Si, Joe S. Matarlo, Yue Yin, Jarrod B. French, Peter J. Tonge, Derek S. Tan
Article
Multidisciplinary Sciences
Kristof Karadi, Sofia M. Kapetanaki, Katalin Raics, Ildiko Pecsi, Robert Kapronczai, Zsuzsanna Fekete, James N. Iuliano, Jinnette Tolentino Collado, Agnieszka A. Gil, Jozsef Orban, Miklos Nyitrai, Greg M. Greetham, Marten H. Vos, Peter J. Tonge, Stephen R. Meech, Andras Lukacs
SCIENTIFIC REPORTS
(2020)
Article
Chemistry, Medicinal
Shabnam Davoodi, Fereidoon Daryaee, Andrew Chang, Stephen G. Walker, Peter J. Tonge
ACS INFECTIOUS DISEASES
(2020)
Article
Chemistry, Multidisciplinary
Adam Hotra, Priya Ragunathan, Pearly Shuyi Ng, Pattarakiat Seankongsuk, Amaravadhi Harikishore, Jickky Palmae Sarathy, Wuan-Geok Saw, Umayal Lakshmanan, Patcharaporn Sae-Lao, Nitin Pal Kalia, Joon Shin, Revathy Kalyanasundaram, Sivaraj Anbarasu, Krupakar Parthasarathy, Chaudhari Namrata Pradeep, Harshyaa Makhija, Peter Droege, Anders Poulsen, Jocelyn Hui Ling Tan, Kevin Pethe, Thomas Dick, Roderick W. Bates, Gerhard Grueber
ANGEWANDTE CHEMIE-INTERNATIONAL EDITION
(2020)
Article
Chemistry, Physical
James N. Iuliano, Christopher R. Hall, Dale Green, Garth A. Jones, Andras Lukacs, Boris Illarionov, Adelbert Bacher, Markus Fischer, Jarrod B. French, Peter J. Tonge, Stephen R. Meech
JOURNAL OF PHYSICAL CHEMISTRY B
(2020)
Article
Chemistry, Medicinal
Yong Li, Fereidoon Daryaee, Grace E. Yoon, Doyoung Noh, Peter M. Smith-Jones, Yuanyuan Si, Stephen G. Walker, Nashaat Turkman, Labros Meimetis, Peter J. Tonge
ACS INFECTIOUS DISEASES
(2020)
Article
Chemistry, Medicinal
Iva Chitrakar, James N. Iuliano, YongLe He, Helena A. Woroniecka, Jinnette Tolentino Collado, Jinelle M. Wint, Stephen G. Walker, Peter J. Tonge, Jarrod B. French
ACS INFECTIOUS DISEASES
(2020)
Article
Chemistry, Physical
Dale Green, Palas Roy, Christopher R. Hall, James N. Iuliano, Garth A. Jones, Andras Lukacs, Peter J. Tonge, Stephen R. Meech
Summary: Flavoproteins that absorb blue light play crucial roles in various photobiological processes. Detailed studies on the excited state structure and dynamics have been conducted, especially through time-resolved vibrational spectroscopy. Although there is generally good agreement between calculated and observed enhancements, some prominently enhanced bands are absent from the calculations, indicating the need for further theoretical development.
JOURNAL OF PHYSICAL CHEMISTRY A
(2021)
Article
Chemistry, Medicinal
Rajeswari Basu, Nan Wang, Sneha Basak, Fereidoon Daryaee, Mustufa Babar, Eleanor K. Allen, Stephen G. Walker, John D. Haley, Peter J. Tonge
Summary: The translation of time-dependent drug-target occupancy to extended pharmacological activity at low drug concentration relies on factors such as target vulnerability and target turnover rate. The study demonstrated a strong correlation between drug-target residence time and postantibiotic effect (PAE) following compound washout, with high target vulnerability and low target resynthesis leading to increased PAE. Moreover, hyperactivity of the fatty acid biosynthesis enzyme FabZ or sub-MIC levels of azithromycin can induce PAE by stabilizing the target enzyme ecLpxC.
ACS INFECTIOUS DISEASES
(2021)
Review
Chemistry, Multidisciplinary
Andras Lukacs, Peter J. Tonge, Stephen R. Meech
Summary: Researchers used time-resolved infrared experiments to investigate the signaling mechanism of light activated proteins. They discovered that the photosensing mechanism of blue light using flavin (BLUF) domain proteins involves non-single-exponential relaxation and a sequential electron and double proton transfer. They also achieved control over the photoactivation process through mutagenesis and unnatural amino acid substitution, and observed real-time changes in protein structural dynamics.
ACCOUNTS OF CHEMICAL RESEARCH
(2022)
Article
Biochemistry & Molecular Biology
Jinnette Tolentino Collado, James N. Iuliano, Katalin Pirisi, Samruddhi Jewlikar, Katrin Adamczyk, Gregory M. Greetham, Michael Towrie, Jeremy R. H. Tame, Stephen R. Meech, Peter J. Tonge, Andras Lukacs
Summary: This study investigates the photoactivation mechanism of OaPAC and reveals the direct connection between BLUF photoactivation and the structural and functional implications on the partner protein. The results demonstrate the formation of an intermediate species on the photoactivation pathway and highlight the essential role of proton transfer in initiating structural reorganization and AC activity.
ACS CHEMICAL BIOLOGY
(2022)
Article
Biochemistry & Molecular Biology
Shabnam Davoodi, Fereidoon Daryaee, James M. Aramini, Jinnette Tolentino Collado, YongLe He, Alyssa C. Pollard, Agnieszka A. Gil, James M. Aramini, Peter J. Tonge
Summary: By mutating the InhA enzyme, this study revealed the role of Y158 in the enzyme mechanism and found that it stabilizes the closed conformation of the enzyme, which is important for designing InhA inhibitors with increased residence times.
Article
Chemistry, Medicinal
Yi-Qian Li, William G. Lannigan, Shabnam Davoodi, Fereidoon Daryaee, Ana Corrionero, Patricia Alfonso, Jose A. Rodriguez-Santamaria, Nan Wang, John D. Haley, Peter J. Tonge
Summary: Researchers have discovered BTK PROTACs based on the selective BTK inhibitor GDC-0853 and the cereblon recruitment ligand pomalidomide. PTD10 is a highly potent BTK degrader that inhibits cell growth and induces apoptosis at lower concentrations than the two parent molecules, as well as three previously reported BTK PROTACs, with improved selectivity compared to ibrutinib-based BTK PROTACs.
JOURNAL OF MEDICINAL CHEMISTRY
(2023)
Article
Biochemistry & Molecular Biology
Julia Fernandez de Luco, Alejandro Recio-Balsells, Diego G. Ghiano, Ana Bortolotti, Juan Manuel Belardinelli, Nina Liu, Pascal Hoffmann, Christian Lherbet, Peter J. Tonge, Babu Tekwani, Hector R. Morbidoni, Guillermo R. Labadie
Summary: Triclosan and isoniazid, known antitubercular compounds, were tested for their leishmanicidal activity using a collection of 37 diverse 1,2,3-triazoles. While some analogs showed activity against Leishmania donovani, there were scarce active compounds against M. tuberculosis. One derivative, 5f, could be a valuable starting point for future antileishmanial drug development, and further investigation is needed to validate a putative leishmanial InhA orthologue as a therapeutic target.
RSC MEDICINAL CHEMISTRY
(2021)
Meeting Abstract
Biophysics
Andras Lukacs, Jinnette Tolentino, James Iuliano, Katalin Pirisi, Peter J. Tonge, Greg Greetham, Mike Towrie, Stephen R. Meech
BIOPHYSICAL JOURNAL
(2020)
