Article
Microbiology
Ji-fang Yu, Jin-tian Xu, Shan-shan Yang, Mei-na Gao, Hao-rui Si, Dong-yan Xiong, Jing Gu, Zhi-long Wu, Jie Zhou, Jiao-yu Deng
Summary: This study identified a methylenetetrahydrofolate reductase (MTHFR) in Mycobacterium tuberculosis and found that its activity is associated with susceptibility to antifolate drugs. These findings have significant implications for the design of antitubercular drugs to treat drug-resistant tuberculosis.
ANTIMICROBIAL AGENTS AND CHEMOTHERAPY
(2022)
Article
Chemistry, Medicinal
Tim Kirkman, Suk Fun Tan, Sair Maximo Chavez-Pacheco, Alexander Hammer, Chris Abell, Manuela Tosin, Anthony G. Coyne, Marcio V. B. Dias
Summary: This study reports the preparation and evaluation of a series of compounds against Mycobacterium tuberculosis DHFR (MtbDHFR). Four compounds in this series showed high affinity against MtbDHFR, with sub-micromolar affinities. Protein crystallography was used to determine the binding mode of six of the best compounds, revealing occupation of an underutilised region of the active site.
Article
Biochemistry & Molecular Biology
Dafeng Liu, Cai Yuan, Chenyun Guo, Mingdong Huang, Donghai Lin
Summary: This study reported the crystal structure and functional mechanism of the CpsY protein in Mycobacterium tuberculosis. The researchers found that CpsY has conserved regions and spacer segments surrounding its catalytic cavity, and the residue R419 is strictly conserved in regulating its phosphotransferase activity. In addition, deletion of certain spacer segments drastically increased the enzyme activity of CpsY.
Article
Biochemistry & Molecular Biology
Muhammad Junaid, Cheng-Dong Li, Jiayi Li, Abbas Khan, Syed Shujait Ali, Syed Baber Jamal, Shah Saud, Arif Ali, Dong-Qing Wei
Summary: The study focused on the resistance mechanisms offered by mutations Q10P, D12A, and G97D in Pyrazinamidase. It was found that Q10P and D12A mutations disrupt the communication among the catalytic triad, affecting the formation of the oxyanion hole and reducing the binding affinity to the drug. These mutations destabilize the interaction between Fe2+ ion and specific residues, ultimately impacting the binding pocket volume and PZA binding. The study provides insight for the design of new and effective PZase inhibitors.
JOURNAL OF BIOMOLECULAR STRUCTURE & DYNAMICS
(2021)
Article
Biochemistry & Molecular Biology
Lamya H. Al-Wahaibi, Althaf Shaik, Mohammed A. Elmorsy, Mohammed S. M. Abdelbaky, Santiago Garcia-Granda, Subbiah Thamotharan, Vijay Thiruvenkatam, Ali A. El-Emam
Summary: This report describes the structural characterization of three 2,4-disubstituted-dihydropyrimidine-5-carbonitrile derivatives, which crystallized in centrosymmetric space groups and adopted an L-shaped conformation. The crystal packing and inter-contacts of these compounds were analyzed based on energy frameworks, and a molecular docking simulation was conducted to evaluate their inhibitory potential against human dihydrofolate reductase (DHFR) enzyme.
Article
Microbiology
Wei Wang, Shanshan Li, Qiping Ge, Haiping Guo, Yuanyuan Shang, Weicong Ren, Yufeng Wang, Zhongtan Xue, Jie Lu, Yu Pang
Summary: This study aimed to establish the critical concentration of para-aminosalicylic acid (PAS) on the Mycobacterial Growth Indicator Tube (MGIT) 960 and determine its resistance mechanism. Results showed that 4 mu g/ml was an appropriate critical concentration to distinguish wild-type and resistotype isolates, and PAS resistance was mainly caused by mutations in thyA and folC genes.
ANNALS OF CLINICAL MICROBIOLOGY AND ANTIMICROBIALS
(2022)
Article
Chemistry, Medicinal
Pooja V. D. Hegde, Michael D. Howe, Matthew Zimmerman, Helena L. M. Boshoff, Sachin Sharma, Brianna Remache, Ziyi D. Jia, Yan Pan, Anthony C. Baughn, Veronique Dartois, Courtney Aldrich
Summary: Tuberculosis is a deadly infectious disease with limited treatment options. Researchers have developed prodrugs and modified the structure of para-Aminosalicylic acid (PAS) to improve its oral bioavailability and reduce rapid clearance. These innovations have the potential to enhance the therapeutic effectiveness of PAS.
EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY
(2022)
Article
Microbiology
Chatpong Pethrak, Navaporn Posayapisit, Jutharat Pengon, Nattida Suwanakitti, Atiporn Saeung, Molnipha Shorum, Kittipat Aupalee, Kritsana Taai, Yongyuth Yuthavong, Sumalee Kamchonwongpaisan, Natapong Jupatanakul
Summary: This study provides important insights into the activity of antifolates as a chemopreventive therapeutic which could lead to a more efficient and cost-effective treatment regime.
ANTIMICROBIAL AGENTS AND CHEMOTHERAPY
(2022)
Article
Immunology
Naveen Thakur, Amar Nath Sharma, Mangesh Dattu Hade, Ajay Chhaya, Ashwani Kumar, Ravinder Singh Jolly, Kanak L. Dikshit
Summary: This study reveals that Mycobacterium tuberculosis produces an unconventional flavohemoglobin (MtbFHb) that can change its conformation and reduce mycothiol disulfide in the presence of D-lactate, protecting the cell from oxidative damage. Overexpression of MtbFHb in M. smegmatis significantly reduces lipid peroxidation and enhances cell survival under oxidative stress.
FRONTIERS IN CELLULAR AND INFECTION MICROBIOLOGY
(2022)
Article
Biochemistry & Molecular Biology
Jiacong Li, Mingxia Yang, Weijia Li, Chujie Lu, Deyu Feng, Zhuo Shang, Chengyuan Wang, Wei Lin
Summary: This study reveals the structure of the non-canonical MTHFR MSMEG_6649 and demonstrates that it has a larger binding groove with FAD compared to canonical MTHFR. The NADH-binding site in MSMEG_6649 is similar to the FAD binding site in canonical MTHFR, suggesting NADH plays the same role in catalysis. Critical residues involved in NADH and substrate binding were identified, providing insights for understanding the catalytic mechanism and potential drug targets.
BIOCHEMICAL JOURNAL
(2023)
Article
Microbiology
Louvina E. van der Laan, Anthony J. Garcia-Prats, H. Simon Schaaf, Maxwell Chirehwa, Jana L. Winckler, Jun Mao, Heather R. Draper, Lubbe Wiesner, Jennifer Norman, Helen McIlleron, Peter R. Donald, Anneke C. Hesseling, Paolo Denti
Summary: Treatment options for children with Rifampicin-resistant tuberculosis (RR-TB) are limited, and the role of para-aminosalicylic acid (PAS) is important in preventing resistance to companion drugs. However, the optimal dosing of PAS in children remains uncertain, and individual adjustment within the WHO-recommended dose range is necessary.
ANTIMICROBIAL AGENTS AND CHEMOTHERAPY
(2022)
Article
Infectious Diseases
Marta Jorba, Marina Pedrola, Ouldouz Ghashghaei, Rocio Herraez, Lluis Campos-Vicens, Franciso Javier Luque, Rodolfo Lavilla, Miguel Vinas
Summary: This study investigates the antimicrobial properties of two trimethoprim-like molecules in combination with sulfamethoxazole, showing significant activity and synergistic effects with colistin. The mechanism of action may involve alterations in bacterial growth kinetics and increased antibiotic entry while reducing efflux pump activity. The interactions between the target enzyme, coenzyme, and studied molecules were explored using enzymology tools and computational chemistry, and a docking-based model was proposed.
Article
Biochemistry & Molecular Biology
A. M. U. B. Mahfuz, Felipe Stambuk Opazo, Luis F. Aguilar, Muhammad Nasir Iqbal
Summary: Carfilzomib has been identified as a potential inhibitor of the ENRs of K. pneumoniae and M. tuberculosis, and it has been shown to exhibit bactericidal activity.
JOURNAL OF BIOMOLECULAR STRUCTURE & DYNAMICS
(2022)
Article
Chemistry, Multidisciplinary
Pooja Asthana, Dhirendra Singh, Jan Skov Pedersen, Mikko J. Hynonen, Ramita Sulu, Abhinandan Murthy, Mikko Laitaoja, Janne Janis, Lee W. Riley, Rajaram Venkatesan
Summary: Mycobacterium tuberculosis relies on lipid import for survival during infection, utilizing transporters like Mce complexes. Structural information on these proteins is lacking, but it is suggested that the SBPs in Mce1-4 may form heterohexamers. The helical domains of MceA-F may play a crucial role in lipid transport.
Article
Microbiology
Fermin Acosta, Miguel Martinez-Lirola, Pedro J. Sola-Campoy, Jon Sicilia, Teresa Guerra-Galan, Sandra R. Maus, Patricia Munoz, Laura Perez-Lago, Dario Garcia de Viedma
Summary: Genotyping tools are crucial for identifying the complexity of transmission clusters in Mycobacterium tuberculosis. This study analyzed the epidemiological and bacteriological complexity of a cluster in Almeria, Spain. The cluster, initially associated with Moroccan migrants, reappeared in Spanish-born individuals, with the identification of two clonal variants. The analysis involved whole-genome sequencing, epidemiological interviews, and characterization of isolates and specimens. The findings revealed the growing cluster with transmitted clonal diversity and amplified within-host diversity due to diagnostic delay. This study highlights the importance of a comprehensive approach in understanding the complexity of tuberculosis transmission events.
MICROBIOLOGY SPECTRUM
(2022)