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Development of New Drugs for an Old Target — The Penicillin Binding Proteins

Astrid Zervosen, Eric Sauvage, Jean-Marie Frère, Paulette Charlier, André Luxen
2012 Molecules  
We present transition state analogs such as boronic acids, which can covalently bind to the active serine residue in the catalytic site.  ...  Some of these novel inhibitors are active against major pathogens, including methicillin-resistant Staphylococcus aureus (MRSA) and thus open avenues new for the discovery of novel antibiotics.  ...  Transition State Analogs Transition state analog inhibitors ( Figure 2 ) have been found to be efficient inhibitors of serine β-lactamases [6, 21, 22] as previously observed for serine proteases [64  ... 
doi:10.3390/molecules171112478 pmid:23095893 fatcat:yvy6shbyufgmfowuxf35gsdoia

Biochemical and Structural Analysis of Inhibitors Targeting the ADC-7 Cephalosporinase of Acinetobacter baumannii

Rachel A. Powers, Hollister C. Swanson, Magdalena A. Taracila, Nicholas W. Florek, Chiara Romagnoli, Emilia Caselli, Fabio Prati, Robert A. Bonomo, Bradley J. Wallar
2014 Biochemistry  
The ADC-7/BATSI complex provides insight into recognition of non-β-lactam inhibitors by ADC enzymes and offers a starting point for the structure-based optimization of this class of novel β-lactamase inhibitors  ...  Currently, β-lactamase inhibitors are structurally similar to β-lactam substrates and are not effective inactivators of this class C cephalosporinase.  ...  (B) Clavulanic acid, a β-lactam-based β-lactamase inhibitor (BLI). (C) Novel boronic acid transition state analog inhibitors (BATSIs).  ... 
doi:10.1021/bi500887n pmid:25380506 pmcid:PMC4263437 fatcat:dpin2jksfrfmlgdfndry55teu4

Carbapenemases [chapter]

Branka Bedenić, Sanda Sardelić
2018 Growing and Handling of Bacterial Cultures [Working Title]  
Carbapenems are stable against wide range of serine-based β-lactamases including extended-spectrum β-lactamases (ESBLs), plasmid-mediated AmpC β-lactamases or against strains with inducible and derepressed  ...  expression of chromosomal AmpC β-lactamases.  ...  There are also several inhibitor-based tests using different inhibitors (EDTA and phenantroline as inhibitors of MBLs, phenylboronic acid as inhibitor of KPC) in combination with carbapenem (e.g., meropenem  ... 
doi:10.5772/intechopen.76282 fatcat:4lgtmbp6cbdpdlfcfz44g2hiaq

Click Chemistry in Lead Optimization of Boronic Acids as β-Lactamase Inhibitors

Emilia Caselli, Chiara Romagnoli, Roza Vahabi, Magdalena A. Taracila, Robert A. Bonomo, Fabio Prati
2015 Journal of Medicinal Chemistry  
Boronic acid transition state inhibitors (BATSIs) represent one of the most promising class of βlactamase inhibitors.  ...  The K i value of the best compound (13a) was as low as 4 nM with significant reduction of bacterial resistance to the combination of cefotaxime/ 13a.  ...  Acknowledgments Funding The Cleveland Department of Veterans Affairs, the Veterans Affairs Merit Review Program award number 1I01BX001974, and the Geriatric Research Education and Clinical Center VISN  ... 
doi:10.1021/acs.jmedchem.5b00341 pmid:26102369 pmcid:PMC5744665 fatcat:ybzl5wuv2fhkxjs24t5mdonn6i

Effects of Phenotype and Genotype on Methods for Detection of Extended-Spectrum- -Lactamase-Producing Clinical Isolates of Escherichia coli and Klebsiella pneumoniae in Norway

S. Tofteland, B. Haldorsen, K. H. Dahl, G. S. Simonsen, M. Steinbakk, T. R. Walsh, A. Sundsfjord
2006 Journal of Clinical Microbiology  
Inhibitor-based test for KPC: The CDT using boronic acid (usually 3-aminophenyulboronic acid) as inhibitor for class A carbapenemases is currently the most extensively used and evaluated method for detection  ...  Inhibitor-based test for MBLs: The ability of EDTA (ethylene diamine tetra-acetic acid) and dipicolinic acid as metal chelating agents for the detection of MBL-producing Enterobacteriaceae has been evaluated  ... 
doi:10.1128/jcm.01319-06 pmid:17079502 pmcid:PMC1828980 fatcat:u3kjemdfcbhzfl3c3edbgcg3oy

NDM Metallo-β-Lactamases and Their Bacterial Producers in Health Care Settings

Wenjing Wu, Yu Feng, Guangmin Tang, Fu Qiao, Alan McNally, Zhiyong Zong
2019 Clinical Microbiology Reviews  
SUMMARY New Delhi metallo-β-lactamase (NDM) is a metallo-β-lactamase able to hydrolyze almost all β-lactams.  ...  Evidence-based guidelines on prevention and control of carbapenem-resistant Gram-negative bacteria are available, although none are specific for NDM-positive strains.  ...  These studies are mainly aimed at CRE as a whole, most of which have serine-based ␤-lactamases, such as KPC and OXA-48, rather than NDM.  ... 
doi:10.1128/cmr.00115-18 pmid:30700432 pmcid:PMC6431124 fatcat:snaihbmlpjdzxb7xugkd6mbi34

Insights into the Antimicrobial Potential of Dithiocarbamate Anions and Metal-Based Species

Chien Ing Yeo, Edward R. T. Tiekink, Jactty Chew
2021 Inorganics  
Overuse and poor disposal of antibacterial agents abet the emergence of bacterial resistance mechanisms. There is a clear need for new approaches for the development of antibacterial therapeutics.  ...  This bibliographic review of the literature points to the exciting potential of dithiocarbamate-based therapeutics in the crucial battle against bacteria.  ...  Unlike other serine-containing beta-lactamases (Classes A, C, and D), the activity of MBLs is not susceptible to beta-lactam inhibitors such as clavulanic acid, sulbactam, and tazobactam [138] .  ... 
doi:10.3390/inorganics9060048 fatcat:irmf4w2nmrahnpl745356bnm3q

Electrophilic Fragment-Based Design of Reversible Covalent Kinase Inhibitors

Rand M. Miller, Ville O. Paavilainen, Shyam Krishnan, Iana M. Serafimova, Jack Taunton
2013 Journal of the American Chemical Society  
Fragment-based ligand design and covalent targeting of noncatalytic cysteines have been employed to develop potent and selective kinase inhibitors.  ...  Using this strategy, we identify electrophilic fragments with sufficient ligand efficiency and selectivity to serve as starting points for the first reported inhibitors of the MSK1 C-terminal kinase domain  ...  The approach is especially wellsuited to the reversible, and hence thermodynamically driven, inhibitors discovered for β-lactamase and RSK2.  ... 
doi:10.1021/ja401221b pmid:23540679 pmcid:PMC3665406 fatcat:d6dcnik7kreqdgsmlg5hwbvyce

Scientific Opinion on Carbapenem resistance in food animal ecosystems

2013 EFSA Journal  
Carbapenems are broad-spectrum β-lactam antimicrobials used for the treatment of serious infections in humans.  ...  Biochemical and phenotypic tests for the confirmatory identification of CP bacteria are available.  ...  Based on their hydrolytic mechanism, carbapenemases are classified into two distinct groups, the serine carbapenemases (with an active site serine) and the metallo-β-lactamases (MBL) (with Zinc [Zn] ions  ... 
doi:10.2903/j.efsa.2013.3501 fatcat:azurwicq5jfqhic32bwle4vgai

Design, Synthesis, and Utility of Defined Molecular Scaffolds

Daisuke Sato, Zhiyuan Wu, Hikaru Fujita, Jonathan S. Lindsey
2021 Organics  
Diverse derivatizable structures—here termed "scaffolds" comprised of "hubs"—provide the foundation for systematic covalent organization of a rich variety of building blocks.  ...  The review covers the history of the field up through 2020, briefly touching on statistically derivatized carriers employed in immunology as counterpoints to the rationally assembled and derivatized scaffolds  ...  triggerable cross-linking; (C) the carbacephem antibiotic Loracarbef as a covalent labeling agent for a mutant β-lactamase, which as part of a fusion protein can bear another molecule (e.g., an enzyme  ... 
doi:10.3390/org2030013 fatcat:kqyohaybivd2jawctszfbqvlju

Boron Chemicals in Drug Discovery and Development: Synthesis and Medicinal Perspective

Bhaskar C Das, Nitesh K Nandwana, Sasmita Das, Varsha Nandwana, Mohammed Adil Shareef, Yogarupa Das, Mariko Saito, Louis M Weiss, Frankis Almaguel, Narayan S Hosmane, Todd Evans
In this review, we collectively represent the current boron-containing drug candidates, boron-containing retinoids, benzoxaboroles, aminoboronic acid, carboranes, and BODIPY, for the treatment of different  ...  Indeed, the spectrum of boron-based entities as drug candidates against many diseases has grown tremendously since the first clinically tested boron-based drug, Velcade.  ...  Acknowledgments: B.D. acknowledges N.I.H. for support R01AI132614-01A1, R21 AA027374-01, 1R01NS109423-01A1. Conflicts of Interest: The authors declare no conflict of interest.  ... 
doi:10.3390/molecules27092615 pmid:35565972 pmcid:PMC9104566 fatcat:o2x4ndq5bzawzgrbwifktjpnsi

Poster presentations

2017 International Journal of Antimicrobial Agents  
Antimicrobial susceptibility was determined by the disk diffusion method, based on performance standards of the Clinical Laboratory Standard Institute in 2016.  ...  A propensity-score-matched analysis was performed to control for the baseline characteristics at bacteremia onset between the Gram-positive and Gram-negative groups.  ...  Acknowledgements: THis study was supported by the Korea Centers for Disease . Keywords: Staphylococcus aureus, vancomycin resistance, VRSA, VISA  ... 
doi:10.1016/s0924-8579(17)30342-4 fatcat:37t5vj7gwrdvri57w3mquptxzq

A fragment-based approach to the identification of novel ketopantoate reductase inhibitors

Amelia Vom
This thesis also describes the risks of false positives in fragment-based identification of KPR inhibitors.  ...  In this study, a fragment-based lead design (FBLD) approach was used to identify small molecule inhibitors of KPR.  ...  His enthusiasm for research is inspiring and his breadth of knowledge in chemistry and more generally astounds me. This has taught me to appreciate science and research so much more.  ... 
doi:10.4225/03/58980e0ceddef fatcat:ipreemfhtvb5vl5t7xhh6lgoku

Strategies to evade resistance: combining biophysical and biochemical approaches to discover compounds addressing new bacterial target systems [article]

Christian Brengel, Universität Des Saarlandes, Universität Des Saarlandes
Biophysical and biochemical test systems are used for identification and characterization of the first hit molecules.  ...  The high content of CYP enzymes encoded in the genome provides a promising base for new drug targets. CYP121 is essential for growth in vitro; CYP125 plays an important role for survival in vivo.  ...  Bacterial strain used in this study was E. coli K12 BL21 DE3 for protein expression. ACKNOWLEDGEMENTS We thank S. Amann and C. Scheid for their help in performing all HPLC-MS/MS-based assays.  ... 
doi:10.22028/d291-23182 fatcat:tggq2giiazf2raqrvqci7fbpzi

I: Catalytic Direct C-H Arylation of Pyrazoles. II: Toward Modulation of Neuroplasticity with Small Molecules

Teresa Jacques
Part II of this thesis addresses two separate targets to modulate neuroplasticity. In Chapter 2, the TrkB receptor as a potential target for pharmacological modulation is examined.  ...  model based on our results is presented.  ...  Acknowledgements ** **** 229 results will be discussed, and future work to narrow down the specific receptor(s) involved in GDNF release by isoquinuclidines will be discussed in Section IV.4 of this chapter  ... 
doi:10.7916/d8794bx2 fatcat:ncvuhwndp5dmpnyxl4aeagmt5a
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