Article
Chemistry, Multidisciplinary
Matthijs J. van Haren, Kamaleddin H. M. E. Tehrani, Ioli Kotsogianni, Nicola Wade, Nora C. Bruchle, Vida Mashayekhi, Nathaniel I. Martin
Summary: The increasing prevalence of metallo-beta-lactamase (MBL)-expressing bacteria is a worrying trend in antibiotic resistance. Studies have shown that zinc ions, which are essential for the hydrolytic activity of MBLs, can be targeted for inhibition. Researchers have developed a series of cephalosporin prodrugs that exhibit potent activity against MBLs and can act synergistically with specific antibiotics.
CHEMISTRY-A EUROPEAN JOURNAL
(2021)
Article
Infectious Diseases
Shamsi Khalid, Antonella Migliaccio, Raffaele Zarrilli, Asad U. Khan
Summary: Investigation on multidrug-resistant New Delhi metallo-beta-lactamase-producing strains found three antibiotic combinations that showed synergistic effects, providing effective treatment options against highly drug-resistant strains.
Article
Chemistry, Medicinal
Liqiang Hu, Huixin Yang, Tao Yu, Fangfang Chen, Runqiu Liu, Shuyuan Xue, Shuangzhan Zhang, Wuyu Mao, Changge Ji, Hao Wang, Hexin Xie
Summary: This study demonstrates the effectiveness of stereochemically altered cephalosporins as potent inhibitors against NDM-1, a major cause of antibiotic resistance. The findings provide a new approach to combat antibiotic resistance.
EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY
(2022)
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
Biology
Zhuoran Zhao, Xiayu Shen, Shuang Chen, Jing Gu, Haun Wang, Maria F. Mojica, Moumita Samanta, Debsindhu Bhowmik, Alejandro J. Vila, Robert A. Bonomo, Shozeb Haider
Summary: Beta-lactam antibiotics are widely used but their efficacy is limited by the spread of beta-lactamases. Inhibitors against class B metallo-beta-lactamases are lacking. The L1 enzyme from Stenotrophomonas maltophilia plays a role in beta-lactam resistance. Conformational changes in elongated loops of L1 affect the active site, and studying these interactions could lead to novel drug development.
Article
Biochemistry & Molecular Biology
Jianzhong Chen, Jinan Wang, Laixue Pang, Wei Wang, Juan Zhao, Weiliang Zhu
Summary: Through molecular dynamics simulations, it was found that binding of double zinc ions induces a closed state of SPM-1, enhancing its conformational stability, while SPM-1 mainly exists in an open conformation when binding with single or non-zinc ions. Additionally, the binding of double zinc ions significantly enhances the interaction network between residues, impacting the stability and catalytic function of SPM-1.
JOURNAL OF BIOMOLECULAR STRUCTURE & DYNAMICS
(2021)
Article
Biochemistry & Molecular Biology
Silvia Gervasoni, James Spencer, Philip Hinchliffe, Alessandro Pedretti, Franco Vairoletti, Graciela Mahler, Adrian J. Mulholland
Summary: This study presents a multiscale approach to model thiol inhibitor binding to IMP-1, demonstrating a reliable computational pipeline that can be applied to inhibitor design for MBLs and other zinc-metalloenzyme systems. The workflow involves molecular simulations, molecular dynamics simulations, QM/MM optimization, and the use of density functional theory to increase the accuracy of predictions. The limitations of empirical models for treating these systems are highlighted, suggesting the need for higher level calculations for reliable structural predictions.
PROTEINS-STRUCTURE FUNCTION AND BIOINFORMATICS
(2022)
Article
Multidisciplinary Sciences
M. Wilamowski, D. A. Sherrell, Y. Kim, A. Lavens, R. W. Henning, K. Lazarski, A. Shigemoto, M. Endres, N. Maltseva, G. Babnigg, S. C. Burdette, V. Srajer, A. Joachimiak
Summary: Serial x-ray crystallography can reveal binding events and chemical conversions during enzymatic reactions. This study used time-resolved serial synchrotron crystallography to analyze the structure, binding, and cleavage of moxalactam antibiotic in L1 metallo-beta-lactamase from Stenotrophomonas maltophilia.
NATURE COMMUNICATIONS
(2022)
Article
Multidisciplinary Sciences
Vikram Khipple Mulligan, Sean Workman, Tianjun Sun, Stephen Rettie, Xinting Li, Liam J. Worrall, Timothy W. Craven, Dustin T. King, Parisa Hosseinzadeh, Andrew M. Watkins, P. Douglas Renfrew, Sharon Guffy, Jason W. Labonte, Rocco Moretti, Richard Bonneau, Natalie C. J. Strynadka, David Baker
Summary: This study presents a structure-guided computational method for designing peptide macrocycles using a mixture of L- and D-amino acids to inhibit therapeutic targets. The experimental results show that this method can effectively predict peptide binding propensity and inhibitory activity, as demonstrated in the interaction with NDM-1.
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
(2021)
Article
Biochemistry & Molecular Biology
Laurent Gavara, Alice Legru, Federica Verdirosa, Laurent Sevaille, Lionel Nauton, Giuseppina Corsica, Paola Sandra Mercuri, Filomena Sannio, Georges Feller, Remi Coulon, Filomena De Luca, Giulia Cerboni, Silvia Tanfoni, Giulia Chelini, Moreno Galleni, Jean-Denis Docquier, Jean-Francois Hernandez
Summary: Researchers are developing compounds based on the 1,2,4-triazole-3-thione scaffold to target resistance mechanisms in Gram-negative bacteria, with promising potential for broad-spectrum inhibitors. These compounds, particularly those containing a carboxylic group at the 4-position, have shown potent inhibition against VIM-type enzymes. Further exploration is needed to improve outer membrane penetration and efficacy against other carbapenemases.
BIOORGANIC CHEMISTRY
(2021)
Article
Biochemistry & Molecular Biology
Lalitha Cheepurupalli, Aathithya Diaz, Adithya Conjeevaram Gopal, Sudarshan Singh Rathore, Vigneshwar Ramakrishnan, Jayapradha Ramakrishnan
Summary: The increase in drug resistance poses a major threat to public health, with carbapenem-resistant bacteria being a significant concern leading to higher morbidity and mortality rates. Inhibiting the activity of New Delhi metallo-beta-lactamase-1 is seen as a potential way to treat multidrug-resistant pathogens. The study identified potential inhibitors for New Delhi metallo-beta-lactamase-1, providing insights into novel treatment strategies for combating drug resistance.
JOURNAL OF BIOMOLECULAR STRUCTURE & DYNAMICS
(2021)
Article
Microbiology
Dennis Nurjadi, Kaan Kocer, Quan Chanthalangsy, Sabrina Klein, Klaus Heeg, Sebastien Boutin
Summary: This study found that the emergence of resistance to Cefiderocol in metallo-beta-lactamase-producing bacteria is facilitated by mutations in the CirA siderophore receptor, which are induced by the New Delhi metallo-beta-lactamase. However, inhibiting the metallo-beta-lactamase activity using dipicolinic acid can successfully prevent the development of Cefiderocol-resistant mutants. Therefore, caution should be taken when using Cefiderocol to treat infections caused by metallo-beta-lactamase-producing bacteria.
ANTIMICROBIAL AGENTS AND CHEMOTHERAPY
(2022)
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
Chemistry, Multidisciplinary
Lingyan Kong, Yilin Zhang, Liwen Yang, Yong Yan, Min Cheng, Xuejun Wang, Le Zhai, Kewu Yang
Summary: The metallo-beta-lactamases (M beta Ls) produced by pathogens pose a challenge to the treatment of bacterial infections worldwide. Oxazolethioacetamides were designed and synthesized as potential M beta Ls inhibitors. Most compounds showed inhibitory activity against M beta L L1, with IC50 values ranging from 0.19 to 0.38 mu M. The fluorine substituted compounds also inhibited VIM-2 with IC50 values ranging from 2.1 to 6.8 mu M. Molecular docking revealed the importance of electron withdrawing groups in the interaction between oxazolethioacetamides and M beta Ls.
Article
Pharmacology & Pharmacy
Yan Guo, Hongtao Liu, Mengge Yang, Rui Ding, Yawen Gao, Xiaodi Niu, Xuming Deng, Jianfeng Wang, Haihua Feng, Jiazhang Qiu
Summary: The study identified dexrazoxane, embelin, candesartan cilexetil, and nordihydroguaiaretic acid as promising carbapenem adjuvants against metallo-β-lactamase-producing carbapenem-resistant bacterial pathogens. These drugs inhibit the activity of metallo-β-lactamases and show in vitro synergistic bactericidal effect with meropenem.
BRITISH JOURNAL OF PHARMACOLOGY
(2023)
Article
Chemistry, Multidisciplinary
Harinarayana Ungati, Vijayakumar Govindaraj, Chithra R. Nair, Govindasamy Mugesh
CHEMISTRY-A EUROPEAN JOURNAL
(2019)
Article
Chemistry, Multidisciplinary
Santanu Mondal, Govindasamy Mugesh
CHEMISTRY-A EUROPEAN JOURNAL
(2019)
Article
Chemistry, Multidisciplinary
Harinarayana Ungati, Vijayakumar Govindaraj, Megha Narayanan, Govindasamy Mugesh
ANGEWANDTE CHEMIE-INTERNATIONAL EDITION
(2019)
Article
Chemistry, Multidisciplinary
Namrata Singh, Govindasamy Mugesh
ANGEWANDTE CHEMIE-INTERNATIONAL EDITION
(2019)
Article
Chemistry, Multidisciplinary
Surendar R. Jakka, Vijayakumar Govindaraj, Govindasamy Mugesh
ANGEWANDTE CHEMIE-INTERNATIONAL EDITION
(2019)
Article
Chemistry, Multidisciplinary
Kishorkumar M. Reddy, Govindasamy Mugesh
CHEMISTRY-A EUROPEAN JOURNAL
(2019)
Review
Chemistry, Multidisciplinary
Vijayakumar Govindaraj, Harinarayana Ungati, Surendar R. Jakka, Sritama Bose, Govindasamy Mugesh
CHEMISTRY-A EUROPEAN JOURNAL
(2019)
Review
Biochemistry & Molecular Biology
Santanu Mondal, Debasish Manna, Karuppusamy Raja, Govindasamy Mugesh
Article
Biochemistry & Molecular Biology
Gaurango Chakrabarty, Somanathapura K. NaveenKumar, Sagar Kumar, Govindasamy Mugesh
ACS CHEMICAL BIOLOGY
(2020)
Article
Chemistry, Multidisciplinary
Namrata Singh, Somanathapura K. NaveenKumar, Motika Geethika, Govindasamy Mugesh
Summary: The study demonstrates that CeVO4 nanozyme can substitute the function of SOD1 and SOD2 in neuronal cells even when the natural enzymes are down-regulated. The nanozyme prevents mitochondrial damage by regulating superoxide levels and restores physiological levels of anti-apoptotic proteins. Additionally, it effectively prevents mitochondrial depolarization and improves cellular ATP levels under oxidative stress.
ANGEWANDTE CHEMIE-INTERNATIONAL EDITION
(2021)
Article
Nanoscience & Nanotechnology
Namrata Singh, Kusaji Pundlik Raul, Aiswarya Poulose, Govindasamy Mugesh, V. Venkatesh
ACS APPLIED BIO MATERIALS
(2020)
Article
Nanoscience & Nanotechnology
Kritika Khulbe, Kapudeep Karmakar, Sourav Ghosh, Kasturi Chandra, Dipshikha Chakravortty, Govindasamy Mugesh
ACS APPLIED BIO MATERIALS
(2020)
Article
Chemistry, Multidisciplinary
Sourav Ghosh, Punarbasu Roy, Sanjay Prasad, Govindasamy Mugesh
Article
Chemistry, Multidisciplinary
Namrata Singh, Mohammed Azharuddin Savanur, Shubhi Srivastava, Patrick D'Silva, Govindasamy Mugesh
Article
Chemistry, Multidisciplinary
Kishorkumar M. Reddy, Govindasamy Mugesh