Article
Biochemistry & Molecular Biology
Jia-Qi Li, Han Gao, Le Zhai, Le-Yun Sun, Cheng Chen, Jia-Zhu Chigan, Huan-Huan Ding, Ke-Wu Yang
Summary: DpC was identified as a potent scaffold for broad-spectrum inhibitors of MβLs, showing good antibacterial effects against multiple bacteria and synergistic action with meropenem.
BIOORGANIC & MEDICINAL CHEMISTRY
(2021)
Article
Chemistry, Medicinal
Anka Lucic, Philip Hinchliffe, Tika R. Malla, Catherine L. Tooke, Jurgen Brem, Karina Calvopina, Christopher T. Lohans, Patrick Rabe, Michael A. McDonough, Timothy Armistead, Allen M. Orville, James Spencer, Christopher J. Schofield
Summary: Penems have shown potential as antibacterials and beta-lactamase inhibitors, but their clinical use is limited compared to carbapenems. Faropenem, with a C-2 tetrahydrofuran ring, is resistant to some beta-lactamases. Studies on reactions of faropenem with beta-lactamases demonstrate different outcomes, suggesting further research is needed for optimizing the interactions between penems and beta-lactamases.
EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY
(2021)
Article
Infectious Diseases
Anka Lucic, Tika R. Malla, Karina Calvopina, Catherine L. Tooke, Jurgen Brem, Michael A. McDonough, James Spencer, Christopher J. Schofield
Summary: This study investigated the reaction of the carbapenem biapenem with different subclasses of beta-lactamases. The results showed the formation of enamine and various types of imine products. The findings support the idea that prolonging the lifetime of beta-lactamase carbapenem complexes by optimizing the tautomerization process could lead to improved carbapenems.
Article
Microbiology
Olga Lomovskaya, Debora Rubio-Aparicio, Ruslan Tsivkovski, Jeff Loutit, Michael Dudley
Summary: The study found that QPX7728 can effectively inhibit a wide range of beta-lactamases, and when combined with carbapenem tebipenem, cephalosporin ceftibuten, and amdinocillin, it can completely reverse beta-lactamase-mediated resistance. In laboratory strains and clinical isolates, the combination of tebipenem and ceftibuten with QPX7728 showed the lowest minimum inhibitory concentrations.
ANTIMICROBIAL AGENTS AND CHEMOTHERAPY
(2022)
Article
Microbiology
Emilio Lence, Concepcion Gonzalez-Bello
Summary: Beta-lactam antibiotics, which represent about 70% of all antibacterial agents in clinical use, have been greatly compromised in their efficacy due to the global dissemination of multi-drug resistant bacteria. The development of effective beta-lactamase inhibitors to combat antibiotic resistance poses significant challenges, given the structural diversity of these enzymes and the emergence of bacterial pathogens capable of producing diverse beta-lactamases simultaneously.
FRONTIERS IN MICROBIOLOGY
(2021)
Article
Biochemistry & Molecular Biology
Han Gao, Jia-Qi Li, Peng-Wei Kang, Jia-Zhu Chigan, Huan Wang, Lu Liu, Yin-Sui Xu, Le Zhai, Ke-Wu Yang
Summary: This study constructed and characterized an effective M beta L inhibitor, which showed preferential inhibition against NDM-1, potential antibacterial activities, and synergistic effects with meropenem. The research provided a new framework for the development of NDM-1 inhibitors.
BIOORGANIC CHEMISTRY
(2021)
Article
Biochemistry & Molecular Biology
Lu Liu, Yin-Sui Xu, Jia-Zhu Chigan, Le Zhai, Huan-Huan Ding, Xiao-Rong Wu, Wei-Ya Chen, Ke-Wu Yang
Summary: The superbug infection mediated by metallo-beta-lactamases has become a serious health threat. In this study, 25 thiosemicarbazone compounds were synthesized and tested for their inhibition of M beta Ls ImiS, NDM-1, and Ll. Compound 2a showed the best inhibitory activity and also exhibited synergistic inhibition with meropenem. These compounds offer a promising scaffold for the development of M beta L inhibitors.
BIOORGANIC CHEMISTRY
(2022)
Article
Biochemistry & Molecular Biology
Jia-Qi Li, Le-Yun Sun, Zhihui Jiang, Cheng Chen, Han Gao, Jia-Zhu Chigan, Huan-Huan Ding, Ke-Wu Yang
Summary: A new scaffold was constructed for inhibiting NDM-1, showing promising results in combating bacterial infections and providing important insights for the development of anti-NDM-1 drugs.
BIOORGANIC CHEMISTRY
(2021)
Article
Immunology
Wen Wang, Shifeng Huang, Chunhong Zou, Yanhui Ding, Huijuan Wang, Shuli Pu, Yunfeng Liao, Hong Du, Deqiang Wang, Liang Chen, Siqiang Niu
Summary: The study demonstrated that AUR enhanced the activity of ATM-AVI against MBL-producing isolates and restored the susceptibility of ATM-AVI resistant mutant strains.
FRONTIERS IN CELLULAR AND INFECTION MICROBIOLOGY
(2021)
Article
Biochemistry & Molecular Biology
Le Zhai, Yue Jiang, Yang Shi, Miao Lv, Ya-Li Pu, Hua-Lei Cheng, Jia-Yu Zhu, Ke-Wu Yang
Summary: The irregular use of antibiotics has led to the development of antibiotic-resistant bacteria, specifically metallo-beta-lactamases. This study identified eight compounds that have strong inhibitory effects on NDM-1, with one compound being the most effective inhibitor. The presence of a hydroxyl group in the compounds was found to improve their inhibitory activity. Additionally, these compounds demonstrated antibacterial effects on NDM-1-producing bacteria and showed low cytotoxicity in cell experiments.
BIOORGANIC CHEMISTRY
(2022)
Article
Microbiology
Tomefa E. Asempa, Hannah Bajor, Jessica H. Mullins, Janice Hartnett, David P. Nicolau
Summary: Research on identifying alternative growth media that better mimic host conditions is increasing. This study evaluated meropenem susceptibility against MBL-harboring Enterobacterales strains in urine, finding lower resistance compared to conventional broth. Factors influencing zinc concentrations in urine and their impact on antibiotic resistance warrant further investigation.
MICROBIOLOGY SPECTRUM
(2021)
Article
Infectious Diseases
Nakita Reddy, Letisha Girdhari, Mbongeni Shungube, Arnoldus C. Gouws, Byron K. Peters, Kamal K. Rajbongshi, Sooraj Baijnath, Sipho Mdanda, Thandokuhle Ntombela, Thilona Arumugam, Linda A. Bester, Sanil D. Singh, Anil Chuturgoon, Per I. Arvidsson, Glenn E. M. Maguire, Hendrik G. Kruger, Thavendran Govender, Tricia Naicker
Summary: This study evaluated the use of a novel beta-lactamase inhibitor, BP2, in combination with meropenem to overcome resistance in hard-to-treat infectious diseases caused by virulent bacteria expressing beta-lactamases. The results showed that BP2 enhanced the activity of meropenem, exhibiting bactericidal effects with a MIC of <= 1 mg/L and was safe to use at the tested concentrations. BP2 also demonstrated strong inhibitory activity against NDM-1 and VIM-2, specifically targeting MBLs. In a murine infection model, the combination of BP2 and meropenem showed significant efficacy. These promising pre-clinical results make BP2 a suitable candidate for further research and development as a metallo-beta-lactamase inhibitor (MBLI).
Article
Biochemistry & Molecular Biology
Nabeela Farhat, Asad U. Khan
Summary: Beta-lactamase is the major resistance factor for beta-lactam antibiotics in Gram-negative bacteria. In this study, potential medications were identified and assessed for blocking beta-lactamases. Several beta-lactamase inhibitors were found and shown to be effective in controlling multidrug resistance.
JOURNAL OF BIOMOLECULAR STRUCTURE & DYNAMICS
(2023)
Article
Microbiology
Xiaopeng Jing, Yanyan Hu, Tingting Wu, Xing Zhang, Shaofeng Luo, Wei Wang, Xiaochun Min, Ruiling Sun, Ji Zeng
Summary: A method using MALDI-TOF MS with EDTA and PB was established to distinguish metallo-beta-lactamase and serine carbapenemases. The method showed high sensitivity and specificity, making it helpful for antibiotic selection in clinical practice.
FRONTIERS IN MICROBIOLOGY
(2023)
Article
Biochemistry & Molecular Biology
Marco J. J. Rotter, Sabrina Zentgraf, Lilia Weizel, Denia Frank, Luisa D. Burgers, Steffen Brunst, Robert Fuerst, Anna Proschak, Thomas A. Wichelhaus, Ewgenij Proschak
Summary: Metallo beta lactamases (MBLs) have become a major problem in treating multidrug-resistant Gram-negative pathogens due to their ability to resist a broad range of drugs and lack of effective inhibitors. In this study, we designed catechol-containing MBL inhibitors that mimic bacterial siderophores, which are actively taken up by bacteria through their iron acquisition system. The most potent catechol-containing MBL inhibitor demonstrated binding to Fe3+ ions and restored the effectiveness of imipenem in NDM-1-expressing K. pneumoniae without affecting healthy cells. These siderophore-containing MBL inhibitors could be a promising strategy to combat MBL-mediated resistance to beta lactam antibiotics.
Article
Multidisciplinary Sciences
Orville A. Pemberton, Radwan E. Noor, Vasantha M. V. Kumar, Ruslan Sanishvili, M. Trent Kemp, Fiona L. Kearns, H. Lee Woodcock, Ioannis Gelis, Yu Chen
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
(2020)
Article
Microbiology
Olga Lomovskaya, Kirk Nelson, Debora Rubio-Aparicio, Ruslan Tsivkovski, Dongxu Sun, Michael N. Dudley
ANTIMICROBIAL AGENTS AND CHEMOTHERAPY
(2020)
Article
Microbiology
Olga Lomovskaya, Ruslan Tsivkovski, Kirk Nelson, Debora Rubio-Aparicio, Dongxu Sun, Maxim Totrov, Michael N. Dudley
ANTIMICROBIAL AGENTS AND CHEMOTHERAPY
(2020)
Article
Microbiology
Kirk Nelson, Debora Rubio-Aparicio, Dongxu Sun, Michael Dudley, Olga Lomovskaya
ANTIMICROBIAL AGENTS AND CHEMOTHERAPY
(2020)
Article
Microbiology
Orville A. Pemberton, Ruslan Tsivkovski, Maxim Totrov, Olga Lomovskaya, Yu Chen
ANTIMICROBIAL AGENTS AND CHEMOTHERAPY
(2020)
Article
Chemistry, Applied
Jillian W. Sheeran, Kiersten Campbell, Christopher P. Breen, Gerald Hummel, Changfeng Huang, Anamika Datta, Serge H. Boyer, Scott J. Hecker, Matthew M. Bio, Yuan-Qing Fang, David D. Ford, M. Grace Russell
Summary: A development-scale reactor has been developed for the efficient preparation of diazomethane, which can effectively separate the product from reagents and byproducts. The reactor design features high productivity, a small reactor volume, a gas liquid separator equipped with a hydrophilic membrane, controlled inventory of CH2N2, and application in esterification and cyclopropanation reactions.
ORGANIC PROCESS RESEARCH & DEVELOPMENT
(2021)
Article
Biochemistry & Molecular Biology
Ian Miller, Max Totrov, Lioubov Korotchkina, Denis N. Kazyulkin, Andrei Gudkov, Sergey Korolev
Summary: Research on L1-EN has revealed that its sequence specificity and catalytic activity are influenced by the conformational properties of the preferred sequence. Unlike other nucleases, L1-EN does not bend the DNA helix, but rather causes 'compression' near the cleavage site, providing multiple advantages for retrotransposition. This work could potentially lead to the development of L1-EN inhibitors as anti-cancer and anti-aging therapeutics.
NUCLEIC ACIDS RESEARCH
(2021)
Article
Chemistry, Applied
Serge H. Boyer, Angela Gonzalez-de-Castro, J. A. Hubertus Dielemans, Laurent Lefort, Zuolin Zhu, Matthias Gnahn, Julia Schoerghuber, Stefan Steinhofer, Andre H. M. de Vries, Scott J. Hecker
Summary: We report a scalable, high-yielding, and highly selective synthesis method for the beta-lactamase inhibitor QPX7728. This method involves two key synthetic steps: nickel-catalyzed boron insertion and enantioselective cyclopropanation. The identification of key reagents for both steps was achieved through high-throughput experimentation. Further optimization allowed for cost-effective and scalable production of QPX7728.
ORGANIC PROCESS RESEARCH & DEVELOPMENT
(2022)
Review
Microbiology
Olga Lomovskaya, Ruslan Tsivkovski, Dongxu Sun, Raja Reddy, Maxim Totrov, Scott Hecker, David Griffith, Jeffery Loutit, Michael Dudley
Summary: QPX7728 is an ultra-broad-spectrum beta-lactamase inhibitor with potent inhibition against a wide range of clinically important beta-lactamases. It is minimally affected by common resistance mechanisms and shows broad coverage when combined with various beta-lactam antibiotics. The oral delivery option of QPX7728 also provides potential for application in combination products.
FRONTIERS IN MICROBIOLOGY
(2021)
Article
Chemistry, Medicinal
K. Raja Reddy, Jonathan Parkinson, Mojgan Sabet, Ziad Tarazi, Serge H. Boyer, Olga Lomovskaya, David C. Griffith, Scott J. Hecker, Michael N. Dudley
Summary: Efforts were made to identify an oral prodrug of beta-lactamase inhibitor clinical candidate QPX7728, and compound 5-Na (QPX7831 Sodium) emerged with optimal properties across all key attributes after synthesizing 17 prodrugs and investigating their key properties.
JOURNAL OF MEDICINAL CHEMISTRY
(2021)
Article
Chemistry, Medicinal
Hanan Almolhim, Sha Ding, Joshua H. Butler, Emily K. Bremers, Grant J. Butschek, Carla Slebodnick, Emilio F. Merino, Zaira Rizopoulos, Maxim Totrov, Maria B. Cassera, Paul R. Carlier
Summary: The tetrahydro-beta-carboline scaffold is a promising structure for the discovery of antimalarial agents. The molecule N2-acyl tetrahydro-beta-carboline GNFP-f-5009 ((+/-)-3b) was found through similarity searching and showed in vitro efficacy against P. falciparum. The enantiomer (R)-3b demonstrated superior pharmacological properties. However, oral efficacy was lacking in mouse testing, possibly due to unfavorable physicochemical properties.
ACS MEDICINAL CHEMISTRY LETTERS
(2022)
Article
Chemistry, Medicinal
Jopaul Mathew, Sha Ding, Kevin A. Kunz, Emily E. Stacy, Joshua H. Butler, Reagan S. Haney, Emilio F. Merino, Grant J. Butschek, Zaira Rizopoulos, Maxim Totrov, Maria B. Cassera, Paul R. Carlier
Summary: Virtual ligand screening using a pharmacophore derived from antimalarial MMV008138 led to the identification of TCMDC-140230 as a compound worth exploring. However, none of the four stereoisomers synthesized showed potent inhibition of Plasmodium falciparum growth, while a minor byproduct 7e exhibited strong in vitro antimalarial activity and was orally efficacious in an in vivo mouse model of malaria.
ACS MEDICINAL CHEMISTRY LETTERS
(2022)
Article
Chemistry, Medicinal
Eugene Raush, Ruben Abagyan, Maxim Totrov
Summary: This paper presents a GCNN-based method for learning and predicting statistical torsional profiles in small organic molecules. By training a specialized GCNN model, it accurately captures various torsional preferences and shows good agreement with quantum chemistry calculations. The application of this method in conformer generation further demonstrates its potential value.
JOURNAL OF CHEMICAL INFORMATION AND MODELING
(2022)