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)
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
Chemistry, Multidisciplinary
Mona M. Katariya, Matthew Snee, Richard B. Tunnicliffe, Madeline E. Kavanagh, Helena I. M. Boshoff, Cecilia N. Amadi, Colin W. Levy, Andrew W. Munro, Chris Abell, David Leys, Anthony G. Coyne, Kirsty J. McLean
Summary: Mycobacterium tuberculosis (Mtb) caused approximately 1.6 million deaths in 2021. Due to the emergence of drug resistance, there is an urgent need for new therapeutic agents and ongoing drug discovery efforts. Host-derived lipids like cholesterol not only support Mtb growth but also play a role in immunomodulation and immune evasion. Mtb cytochrome P450 (CYP) enzymes, particularly CYP125 and CYP142, are potential targets for inhibition in lipid catabolism. Compounds based on an ethyl 5-(pyridin-4-yl)-1H-indole-2-carboxylate pharmacophore showed strong binding to both CYP125 and CYP142, with in-cell activity against drug-resistant isolates. These findings are important for developing additional treatment options and exploring the role of CYP125 and CYP142 in Mtb pathogenesis.
CHEMISTRY-A EUROPEAN JOURNAL
(2023)
Article
Oncology
Jonathan Blachier, Aurore Cleret, Nathalie Guerin, Clara Gil, Jean-Marc Fanjat, Florian Tavernier, Laura Vidault, Fanny Gallix, Nicolas Rama, Rodrigue Rossignol, Diana Piedrahita, Aurely Andrivon, Marie Chalons-Cottavoz, Karine Aguera, Fabien Gay, Francoise Horand, Bastien Laperrousaz
Summary: L-Asparaginase is critical in ALL therapy, but its efficacy in solid tumors is unclear due to ASNS expression. However, it has a glutaminase activity in pancreatic cancer. By studying L-Asparaginase-resistant pancreatic cancer cells, we identified GS as a marker of resistance and its correlation with L-Asparaginase efficacy in various cancer cell lines. Furthermore, GS inhibition prevents cancer cell adaptation to L-Asparaginase-induced glutamine starvation, suggesting potential drug combinations to overcome resistance.
EXPERIMENTAL CELL RESEARCH
(2023)
Article
Chemistry, Multidisciplinary
Xin Lin, Julia L. Kurz, Khushboo M. Patel, Shun Jie Wun, Waleed M. Hussein, Thierry Lonhienne, Nicholas P. West, Ross P. McGeary, Gerhard Schenk, Luke W. Guddat
Summary: Researchers screened a potential drug, NSC116565, targeting a new target KARI to combat drug-resistant tuberculosis, showing promising results in inhibiting Mycobacterium tuberculosis growth and validating KARI as a TB drug target.
CHEMISTRY-A EUROPEAN JOURNAL
(2021)
Article
Chemistry, Medicinal
Allan H. Pang, Keith D. Green, Nishad Thamban Chandrika, Atefeh Garzan, Ankita Punetha, Selina Y. L. Holbrook, Melisa J. Willby, James E. Posey, Oleg V. Tsodikov, Sylvie Garneau-Tsodikova
Summary: Eis acetyltransferase is a clinically significant mechanism of tuberculosis resistance to kanamycin. Inhibitors of Eis have been discovered, which can effectively abolish resistance to kanamycin in highly resistant strains. Additionally, several compounds with toxic effects on mycobacteria have been identified, with a mechanism of toxicity distinct from Eis inhibition.
EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY
(2022)
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
Chemistry, Physical
Kabelo B. Dilebo, Njabulo J. Gumede, Winston Nxumalo, Thabe M. Matsebatlela, Dikgale Mangokoana, Ngaoko R. Moraone, Bernard Omondi, Richard M. Mampa
Summary: A series of quinazolines were successfully synthesized via Sonogashira cross-coupling and dechloroamination reactions, showing potential anti-Mycobacterium tuberculosis properties with promising minimum inhibitory concentrations. The possible mode of interaction with Mtb was theoretically explained through molecular protein 3ZXR, revealing the compounds' SAR to MtGS.
JOURNAL OF MOLECULAR STRUCTURE
(2021)
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, Medicinal
Heng Wang, Jing Bi, Yuan Zhang, Miaomiao Pan, Qinglong Guo, Genhui Xiao, Yumeng Cui, Song Hu, Chi Kin Chan, Ying Yuan, Takushi Kaneko, Guoliang Zhang, Shawn Chen
Summary: This study identifies linsitinib, a clinical-stage drug originally targeting kinase IGF1R/IR, as a potent inhibitor of the essential glutamine synthase in Mycobacterium tuberculosis. Linsitinib also improves autophagy flux and reduces intracellular growth of Mtb. These findings suggest that targeting ATP-dependent enzymes like glutamine synthase could be a novel approach for anti-TB therapy.
ACS INFECTIOUS DISEASES
(2022)
Article
Biochemistry & Molecular Biology
Da-Gyum Lee, Yoo-Hyun Hwang, Eun-Jin Park, Jung-Hyun Kim, Sung-Weon Ryoo
Summary: The study identified the drug clomiphene citrate (CC) as a potential treatment for M. abscessus infections, inhibiting the growth of both wild-type strains and resistant strains, as well as showing efficacy against biofilm. CC did not exhibit cytotoxicity in infected cells, suggesting its potential as a new drug therapy for M. abscessus infections.
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
(2021)
Article
Multidisciplinary Sciences
Casey M. Stevens, Svitlana O. Babii, Amitkumar N. Pandya, Wei Li, Yupeng Li, Jitender Mehla, Robyn Scott, Pooja Hegde, Pavan K. Prathipati, Atanu Acharya, Jinchan Liu, James C. Gumbart, Jeffrey North, Mary Jackson, Helen I. Zgurskaya
Summary: In this study, the researchers successfully purified and reconstituted MmpL3 and CmpL1 proteins into proteoliposomes. The proteins were found to facilitate proton translocation across a phospholipid bilayer, but they differed in their pH responses and interactions with substrate mimics and inhibitors.
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
(2022)
Article
Microbiology
Gregory S. Basarab, Sandeep Ghorpade, Liezl Gibhard, Rudolf Mueller, Mathew Njoroge, Nashied Peton, Preshendren Govender, Lisa M. Massoudi, Gregory Thomas Robertson, Anne J. Lenaerts, Helena Ingrid Boshoff, Douglas Joerss, Tanya Parish, Thomas F. Durand-Reville, Manos Perros, Vinayak Singh, Kelly Chibale
Summary: This article describes a series of spiropyrimidinetrione (SPT) compounds with activity against Mycobacterium tuberculosis by inhibiting DNA gyrase. The SPT class of compounds operates through a novel mode of inhibition, which is not cross-resistant with other DNA gyrase-inhibiting antibacterials. Compound 22 from the series demonstrated in vitro cidality and intracellular activity against M. tuberculosis. The DNA gyrase mode of action was supported by inhibition of the target in a DNA supercoiling assay and elicitation of an SOS response in M. tuberculosis.
ANTIMICROBIAL AGENTS AND CHEMOTHERAPY
(2022)
Review
Chemistry, Medicinal
Vladimir Finger, Martin Kufa, Ondrej Soukup, Daniele Castagnolo, Jaroslav Roh, Jan Korabecny
Summary: This review provides an overview of recent advances in the hit-to-lead drug discovery studies of pyrimidine-containing compounds with antitubercular activity, focusing on their structural diversity. The review discusses the targets and structure-activity relationships of different pyrimidine families in the first part and categorizes unexplored or speculative targets of antitubercular pyrimidine derivatives based on their structural types in the second part.
EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY
(2023)
