Article
Chemistry, Medicinal
Yanran Lu, Sandip Vibhute, Linsen Li, Antony Okumu, Steven C. Ratigan, Sheri Nolan, Jonathan L. Papa, Chelsea A. Mann, Anthony English, Anna Chen, Justin T. Seffernick, Bryan Koci, Leonard R. Duncan, Brieanna Roth, Jason E. Cummings, Richard A. Slayden, Steffen Lindert, Craig A. McElroy, Daniel J. Wozniak, Jack Yalowich, Mark J. Mitton-Fry
Summary: Novel bacterial topoisomerase inhibitors (NBTIs) are promising new antibiotics with lead compound 79 showing potent antibacterial activity, low resistance, favorable cardiovascular safety profile, and in vivo efficacy against methicillin-resistant Staphylococcus aureus.
JOURNAL OF MEDICINAL CHEMISTRY
(2021)
Article
Chemistry, Medicinal
Maja Kokot, Irena Zdovc, Lidija Senerovic, Natasa Radakovic, Marko Anderluh, Nikola Minovski, Martina Hrast
Summary: Novel bacterial topoisomerase inhibitors (NBTIs) are promising antimicrobials for multidrug-resistant bacterial infections. However, the challenge lies in balancing antibacterial activity and hERG-related toxicity. A new optimization strategy led to the development of compound 12, which showed potent antibacterial activity against Gram-positive bacteria, reduced hERG inhibition, no cardiotoxicity, and effective in vivo efficacy against MRSA infection.
EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY
(2023)
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)
Review
Biochemistry & Molecular Biology
Vita Vidmar, Marlene Vayssieres, Valerie Lamour
Summary: DNA topoisomerases play a crucial role in resolving topological problems in DNA. They can recognize DNA topology and catalyze various reactions by cutting and rejoining DNA. While the mechanisms of DNA cleavage and re-ligation have been extensively studied, the structural rearrangements required for DNA-gate opening and strand transfer, especially in type IA topoisomerases, remain unclear.
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
(2023)
Review
Biochemistry & Molecular Biology
Julia A. Hotinger, Heather A. Pendergrass, Aaron E. May
Summary: The type III secretion system (T3SS) is a virulence apparatus used by many Gram-negative pathogenic bacteria to cause infections. Pathogens utilizing T3SS are responsible for millions of infections yearly. The T3SS has emerged as an attractive anti-virulence target for therapeutic design due to its complexity and the potential to directly target components.
Article
Chemistry, Medicinal
Amanda Lyons, James Kirkham, Kevin Blades, David Orr, Elizabeth Dauncey, Oliver Smith, Emma Dick, Rolf Walker, Teresa Matthews, Adam Bunt, Jonathan Finlayson, Ian Morrison, Victoria J. Savage, Emmanuel Moyo, Hayley S. Butler, Rebecca Newman, Nicola Ooi, Andrew Smith, Cedric Charrier, Andrew J. Ratcliffe, Neil R. Stokes, Stuart Best, Anne-Marie Salisbury, Mark Craighead, Ian R. Cooper
Summary: There is an urgent need for novel antibiotic drugs to treat infections caused by antibiotic-resistant pathogens. The identified novel series of bicyclic-oxazolidinone inhibitors of bacterial type II topoisomerase show potent broad-spectrum anti-bacterial activity, including against multidrug-resistant strains, and have a promising in vitro safety profile.
BIOORGANIC & MEDICINAL CHEMISTRY LETTERS
(2022)
Article
Microbiology
Johanne Blais, Charles R. Dean, Guillaume Lapointe, Jennifer A. Leeds, Sylvia Ma, Laura Morris, Heinz E. Moser, Colin S. Osborne, Katherine R. Prosen, Daryl Richie, Colin Skepper, Katherine Thompson, Jason Vo, Qin Yue, Alexey Rivkin
Summary: CUO246 is a novel DNA gyrase/topoisomerase IV inhibitor with broad-spectrum in vitro activity against Gram-positive, fastidious Gram-negative, and atypical bacterial pathogens, including quinolone-resistant strains. It inhibits both DNA gyrase and topoisomerase IV and exhibits potent bactericidal activity. In a mouse model, it shows efficacy against S. aureus infections. CUO246 may be a useful treatment option for acute skin and skin structure infections, respiratory tract infections, and sexually transmitted infections.
ANTIMICROBIAL AGENTS AND CHEMOTHERAPY
(2022)
Article
Immunology
Bashir Lawal, Yu-Cheng Kuo, Maryann Rachmawati Sumitra, Alexander T. H. Wu, Hsu-Shan Huang
Summary: The study evaluated the therapeutic potential and pharmacokinetic properties of a novel compound HH-N25 in breast cancer treatment. Results showed that HH-N25 exhibited potent anticancer activity against human breast cancer cell lines and extended survival duration in mouse models without causing unacceptable toxicities based on body weight changes.
JOURNAL OF INFLAMMATION RESEARCH
(2021)
Article
Environmental Sciences
Fatma Haddaji, Adele Papetti, Emira Noumi, Raffaella Colombo, Sumukh Deshpande, Kaiss Aouadi, Mohd Adnan, Adel Kadri, Boulbaba Selmi, Mejdi Snoussi
Summary: The study identified phytochemical compounds with antioxidant and antimicrobial properties from P. tomentosa extracts, showing potential to become potent antimicrobial agents. Molecular docking study revealed high binding affinity of certain compounds to target proteins, indicating promise for drug discovery and development.
ENVIRONMENTAL SCIENCE AND POLLUTION RESEARCH
(2021)
Article
Microbiology
Ivone Jimenez-Toro, Carlos A. Rodriguez, Andres F. Zuluaga, Julian D. Otalvaro, Hector Perez-Madrid, Omar Vesga
Summary: Combination therapy with ampicillin plus ceftriaxone is the first-line treatment for severe infections caused by Enterococcus faecalis, but the pharmacokinetic/pharmacodynamic index linked to its efficacy has not been defined yet, hindering dose optimization in clinical settings.
ANTIMICROBIAL AGENTS AND CHEMOTHERAPY
(2023)
Review
Chemistry, Medicinal
Jigar Desai, S. Sachchidanand, Sanjay Kumar, Rajiv Sharma
Summary: Inhibition of bacterial DNA gyrase and topoisomerase IV has become a promising strategy for treating infections caused by antibiotic-resistant bacteria. The Novel Bacterial Topoisomerase Inhibitors (NBTIs) bind to a different site than fluoroquinolones, with a novel mechanism to avoid existing bacterial resistance. Ongoing efforts in structural modifications have significant impacts on the general properties of inhibitors.
EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY REPORTS
(2021)
Article
Microbiology
Hongliang Zhao, Susan Eszterhas, Jacob Furlon, Hao Cheng, Karl E. Griswold
Summary: Research on lysostaphin revealed that binding affinity, rather than intrinsic catalytic firepower, is the dominant factor in its efficacy. Tuning lysostaphin through electrostatic affinity can enhance performance and potentially improve in vivo efficacy. This study provides important insights into the complex relationships between lysin electrostatics, bacterial targeting, cell lysis efficiency, and in vivo efficacy.
ANTIMICROBIAL AGENTS AND CHEMOTHERAPY
(2021)
Article
Infectious Diseases
Maja Kokot, Doroteja Novak, Irena Zdovc, Marko Anderluh, Martina Hrast, Nikola Minovski
Summary: Novel bacterial topoisomerase inhibitors (NBTIs) are effective antibacterial agents that target bacterial type II topoisomerases. The crystal structure of an NBTI ligand complex with DNA gyrase and DNA showed that halogen atom in the phenyl RHS moiety can establish strong halogen bonds with the enzyme, which contribute to the inhibitory potency and antibacterial activity of NBTIs. Further investigations revealed that hydrogen-bonding interactions are not feasible, while hydrophobic and halogen-bonding interactions are possible.
Article
Chemistry, Medicinal
Krishnaiah Maddeboina, Sravan K. Jonnalagadda, Ahmed Morsy, Ling Duan, Yashpal S. Chhonker, Daryl J. Murry, Trevor M. Penning, Paul C. Trippier
Summary: AKR1C3 is overexpressed in castration-resistant prostate cancer and drives proliferation and aggressiveness by producing androgens. The study reports the optimization of AKR1C3 inhibitors and the discovery of a potent inhibitor, 5r, with high selectivity for AKR1C3. A prodrug strategy was used to improve pharmacokinetics, and the prodrug 4r was converted to the active form, 5r. In vivo experiments showed increased exposure and concentration of 5r compared to direct administration of the free acid. The prodrug 4r effectively reduced tumor volume without toxicity.
JOURNAL OF MEDICINAL CHEMISTRY
(2023)
Article
Biochemistry & Molecular Biology
Dharaminder Singh, Sudhir P. Deosarkar, Elaine Cadogan, Vikki Flemington, Alysha Bray, Jingwen Zhang, Ronald S. Reiserer, David K. Schaffer, Gregory B. Gerken, Clayton M. Britt, Erik M. Werner, Francis D. Gibbons, Tomasz Kostrzewski, Christopher E. Chambers, Emma J. Davies, Antonio Ramos Montoya, Jacqueline H. L. Fok, David Hughes, Kristin Fabre, Matthew P. Wagoner, John P. Wikswo, Clay W. Scott
Summary: Conventional in vitro model systems fail to replicate the concentration changes of drugs observed in vivo, reducing the predictability of data. This study introduces a novel microfluidic device, the Microformulator, which allows cells to be cultured with in vivo-like pharmacokinetic profiles, improving the understanding of the impact of pharmacokinetics on biological responses.
Correction
Biochemistry & Molecular Biology
Thomas Germe, Judit Voros, Frederic Jeannot, Thomas Taillier, Robert A. Stavenger, Eric Bacque, Anthony Maxwell, Benjamin D. Bax
NUCLEIC ACIDS RESEARCH
(2018)
Article
Biochemistry & Molecular Biology
Thomas Germe, Judit Voros, Frederic Jeannot, Thomas Taillier, Robert A. Stavenger, Eric Bacque, Anthony Maxwell, Benjamin D. Bax
NUCLEIC ACIDS RESEARCH
(2018)
Article
Chemistry, Medicinal
Elizabeth G. Gibson, Tim R. Blower, Monica Cacho, Ben Bax, James M. Berger, Neil Osheroff
ACS INFECTIOUS DISEASES
(2018)
Article
Biochemistry & Molecular Biology
Satya Prathyusha Bhamidimarri, Michael Zahn, Jigneshkumar Dahyabhai Prajapati, Christian Schleberger, Sandra Soederholm, Jennifer Hoover, Josh West, Ulrich Kleinekathoefer, Dirk Bumann, Mathias Winterhalter, Bert van den Berg
Review
Microbiology
Jurgen B. Bulitta, William W. Hope, Ann E. Eakin, Tina Guina, Vincent H. Tam, Arnold Louie, George L. Drusano, Jennifer L. Hoover
ANTIMICROBIAL AGENTS AND CHEMOTHERAPY
(2019)
Article
Biochemistry & Molecular Biology
Saba Dehghani-Tafti, Vladimir Levdikov, Alfred A. Antson, Ben Bax, Cyril M. Sanders
NUCLEIC ACIDS RESEARCH
(2019)
Article
Chemistry, Medicinal
Elizabeth G. Gibson, Ben Bax, Pan F. Chan, Neil Osheroff
ACS INFECTIOUS DISEASES
(2019)
Article
Microbiology
Jennifer L. Hoover, Christine M. Singley, Philippa Elefante, Stephen Rittenhouse
ANTIMICROBIAL AGENTS AND CHEMOTHERAPY
(2019)
Article
Chemistry, Medicinal
Reema K. Thalji, Kaushik Raha, Daniele Andreotti, Anna Checchia, Haifeng Cui, Giovanni Meneghelli, Roberto Profeta, Federica Tonelli, Simona Tommasi, Tania Bakshi, Brian T. Donovan, Alison Howells, Shruti Jain, Christopher Nixon, Geoffrey Quinque, Lynn McCloskey, Benjamin D. Bax, Margarete Neu, Pan F. Chan, Robert A. Stavenger
BIOORGANIC & MEDICINAL CHEMISTRY LETTERS
(2019)
Review
Biochemistry & Molecular Biology
Benjamin D. Bax, Garib Murshudov, Anthony Maxwell, Thomas Germe
JOURNAL OF MOLECULAR BIOLOGY
(2019)
Article
Biochemical Research Methods
Chloe R. Koulouris, Benjamin D. Bax, John R. Atack, S. Mark Roe
ACTA CRYSTALLOGRAPHICA SECTION F-STRUCTURAL BIOLOGY COMMUNICATIONS
(2020)
Article
Biochemical Research Methods
Gareth D. Fenn, Helen Waller-Evans, John R. Atack, Benjamin D. Bax
ACTA CRYSTALLOGRAPHICA SECTION F-STRUCTURAL BIOLOGY COMMUNICATIONS
(2020)
Article
Biochemistry & Molecular Biology
Karen T. Elvers, Magdalena Lipka-Lloyd, Rebecca C. Trueman, Benjamin D. Bax, Youcef Mehellou
Summary: The research focuses on the mechanism by which SPAK and OSR1 kinases regulate the function of ion co-transporters through phosphorylation, and the potential strategy of inhibiting them by inhibiting their binding with WNK kinases. Crystal structure studies revealed a highly conserved primary pocket and a flexible secondary pocket. Additionally, the affinity of CCT domains to short peptides derived from WNK4 and NKCC1 was evaluated using a biophysical approach.
Article
Chemistry, Medicinal
Jo Ann W. Byl, Rudolf Mueller, Ben Bax, Gregory S. Basarab, Kelly Chibale, Neil Osheroff
Summary: Novel Spiropyrimidinetriones (SPTs) compounds have been found to effectively target drug-resistant tuberculosis by working on bacterial DNA gyrase. These compounds show similar or even greater activity compared to fluoroquinolone antibacterials, and they can overcome common mutations associated with fluoroquinolone resistance. Moreover, they have low activity against human topoisomerase II alpha.
ACS INFECTIOUS DISEASES
(2023)
Meeting Abstract
Pharmacology & Pharmacy
S. K. Drescher, D. Tenero, D. Austin, J. Hoover, N. Goyal
CLINICAL PHARMACOLOGY & THERAPEUTICS
(2018)
Article
Chemistry, Medicinal
Shibin Zhao, Julian Maceren, Mia Chung, Samantha Stone, Raphael Geiben, Melissa L. Boby, Bradley S. Sherborne, Derek S. Tan
Summary: Antibiotic resistance is a major threat to public health, with Gram-negative bacteria presenting unique challenges due to their low permeability and efflux pumps. Limited understanding of the chemical rules for overcoming these barriers hinders antibacterial drug discovery. Efforts to address this issue, such as screening compound libraries and using cheminformatic analysis, have led to the design of sulfamidoadenosines with diverse substituents, showing potential utility in accumulation in Escherichia coli.
BIOORGANIC & MEDICINAL CHEMISTRY LETTERS
(2024)
Article
Chemistry, Medicinal
Jichun Li, Qing Li, Shuai Xia, Jiahuang Tu, Longbo Zheng, Qian Wang, Shibo Jiang, Chao Wang
Summary: This study successfully developed a short peptide mimetic as a MERS-CoV fusion inhibitor by reproducing the key recognition features of the HR2 helix. The resulting 23-mer lipopeptide showed comparable inhibitory effect to the 36-mer HR2 peptide HR2P-M2. This has important implications for developing short peptide-based antiviral agents to treat MERS-CoV infection.
BIOORGANIC & MEDICINAL CHEMISTRY LETTERS
(2024)
Article
Chemistry, Medicinal
Krista Jaunsleine, Linda Supe, Jana Spura, Sten van Beek, Anna Sandstrom, Jessica Olsen, Carina Halleskog, Tore Bengtsson, Ilga Mutule, Benjamin Pelcman
Summary: Beta(2)-adrenergic receptor agonists can stimulate glucose uptake by skeletal muscle cells and are therefore potential treatments for type 2 diabetes. The chirality of compounds has a significant impact on the activity of these agonists. This study found that certain synthesized compounds showed higher glucose uptake activity. These findings provide important information for the design of novel beta(2)AR agonists for T2D treatment.
BIOORGANIC & MEDICINAL CHEMISTRY LETTERS
(2024)
Article
Chemistry, Medicinal
Xin Xu, Jia Chen, Guan Wang, Xiaojuan Zhang, Qiang Li, Xiaobo Zhou, Fengying Guo, Min Li
Summary: The study focuses on EZH2, a promising therapeutic target for various types of cancers. Researchers designed and synthesized a series of novel derivatives aiming to enhance the EZH2 inhibition activity. Among them, compound 28 displayed potent EZH2 inhibition activity and showed high anti-proliferative effects in lymphoma cell lines and xenograft mouse models. The study suggests that compound 28 has potential as a therapeutic candidate for EZH2-associated cancers.
BIOORGANIC & MEDICINAL CHEMISTRY LETTERS
(2024)
Article
Chemistry, Medicinal
Wei Zhang, Wei Liu, Ya-Dong Zhao, Li-Zi Xing, Ji Xu, Rui-Jun Li, Yun-Xiao Zhang
Summary: This study developed a series of aromatic amide derivatives based on Rhein and investigated their inhibitory activity against alpha-Syn aggregation. Two of these compounds showed promising potential in treating Parkinson's disease by stabilizing alpha-Syn's conformation and disassembling alpha-Syn oligomers and fibrils.
BIOORGANIC & MEDICINAL CHEMISTRY LETTERS
(2024)
Article
Chemistry, Medicinal
Mani Sharma, S. S. S. S. Sudha Ambadipudi, Neeraj Kumar Chouhan, V. Lakshma Nayak, Srihari Pabbaraja, Sai Balaji Andugulapati, Ramakrishna Sistla
Summary: Therapeutically active lipids in drug delivery systems can enhance the safety and efficacy of treatment. The liposome formulation created using synthesized biologically active lipids showed additive anti-cancer effects and reduced tumorigenic potential.
BIOORGANIC & MEDICINAL CHEMISTRY LETTERS
(2024)
