High throughput screening to determine the antibacterial activity of Terminalia ferdinandiana (Kakadu plum): A proof of concept

2021 ◽  
Vol 182 ◽  
pp. 106169
Author(s):  
Saleha Akter ◽  
Yasmina Sultanbawa ◽  
Daniel Cozzolino
Keyword(s):  
Antibacterial Activity ◽  
High Throughput ◽  
High Throughput Screening ◽  
Proof Of Concept ◽  
Kakadu Plum ◽  
Terminalia Ferdinandiana

Large-scale High-throughput Screening Revealed 5'-(carbonylamino)-2,3'- bithiophene-4'-carboxylate as Novel Template for Antibacterial Agents

2020 ◽  
Vol 17 (5) ◽  
pp. 716-724
Author(s):  
Yan A. Ivanenkov ◽  
Renat S. Yamidanov ◽  
Ilya A. Osterman ◽  
Petr V. Sergiev ◽  
Vladimir A. Aladinskiy ◽  
...  
Keyword(s):  
Antibacterial Activity ◽  
High Throughput ◽  
High Throughput Screening ◽  
Large Scale ◽  
Antibacterial Agents ◽  
Sos Response ◽  
Luciferase Assay ◽  
Translational Machinery ◽  
E Coli ◽  
New Class

Background: The key issue in the development of novel antimicrobials is a rapid expansion of new bacterial strains resistant to current antibiotics. Indeed, World Health Organization has reported that bacteria commonly causing infections in hospitals and in the community, e.g. E. Coli, K. pneumoniae and S. aureus, have high resistance vs the last generations of cephalosporins, carbapenems and fluoroquinolones. During the past decades, only few successful efforts to develop and launch new antibacterial medications have been performed. This study aims to identify new class of antibacterial agents using novel high-throughput screening technique. Methods: We have designed library containing 125K compounds not similar in structure (Tanimoto coeff.< 0.7) to that published previously as antibiotics. The HTS platform based on double reporter system pDualrep2 was used to distinguish between molecules able to block translational machinery or induce SOS-response in a model E. coli system. MICs for most active chemicals in LB and M9 medium were determined using broth microdilution assay. Results: In an attempt to discover novel classes of antibacterials, we performed HTS of a large-scale small molecule library using our unique screening platform. This approach permitted us to quickly and robustly evaluate a lot of compounds as well as to determine the mechanism of action in the case of compounds being either translational machinery inhibitors or DNA-damaging agents/replication blockers. HTS has resulted in several new structural classes of molecules exhibiting an attractive antibacterial activity. Herein, we report as promising antibacterials. Two most active compounds from this series showed MIC value of 1.2 (5) and 1.8 μg/mL (6) and good selectivity index. Compound 6 caused RFP induction and low SOS response. In vitro luciferase assay has revealed that it is able to slightly inhibit protein biosynthesis. Compound 5 was tested on several archival strains and exhibited slight activity against gram-negative bacteria and outstanding activity against S. aureus. The key structural requirements for antibacterial potency were also explored. We found, that the unsubstituted carboxylic group is crucial for antibacterial activity as well as the presence of bulky hydrophobic substituents at phenyl fragment. Conclusion: The obtained results provide a solid background for further characterization of the 5'- (carbonylamino)-2,3'-bithiophene-4'-carboxylate derivatives discussed herein as new class of antibacterials and their optimization campaign.

scholarly journals Cross-Platform Bayesian Optimization System for Autonomous Biological Assay Development

2021 ◽  
Vol 26 (6) ◽  
pp. 579-590
Author(s):  
Sam Elder ◽  
Carleen Klumpp-Thomas ◽  
Adam Yasgar ◽  
Jameson Travers ◽  
Shayne Frebert ◽  
...  
Keyword(s):  
High Throughput ◽  
High Throughput Screening ◽  
Assay Development ◽  
Bayesian Optimization ◽  
Biological Assay ◽  
Proof Of Concept ◽  
Screening Assay ◽  
High Throughput Screening Assay ◽  
Cross Platform ◽  
Assay Conditions

Current high-throughput screening assay optimization is often a manual and time-consuming process, even when utilizing design-of-experiment approaches. A cross-platform, Cloud-based Bayesian optimization-based algorithm was developed as part of the National Center for Advancing Translational Sciences (NCATS) ASPIRE (A Specialized Platform for Innovative Research Exploration) Initiative to accelerate preclinical drug discovery. A cell-free assay for papain enzymatic activity was used as proof of concept for biological assay development and system operationalization. Compared with a brute-force approach that sequentially tested all 294 assay conditions to find the global optimum, the Bayesian optimization algorithm could find suitable conditions for optimal assay performance by testing 21 assay conditions on average, with up to 20 conditions being tested simultaneously, as confirmed by repeated simulation. The algorithm could achieve a sevenfold reduction in costs for lab supplies and high-throughput experimentation runtime, all while being controlled from a remote site through a secure connection. Based on this proof of concept, this technology is expected to be applied to more complex biological assays and automated chemistry reaction screening at NCATS, and should be transferable to other institutions. Graphical Abstract

A proof-of-concept study: evaluating the applicability of high-throughput screening data and read-across tools for food relevant chemicals

2018 ◽  
Vol 295 ◽  
pp. S142
Author(s):  
J.L. Nguyen ◽  
A. Maier ◽  
J. Ovesen ◽  
N. Kleinstreuer ◽  
R. Judson ◽  
...  
Keyword(s):  
High Throughput ◽  
High Throughput Screening ◽  
Proof Of Concept ◽  
Concept Study

scholarly journals An exposure:activity profiling method for interpreting high-throughput screening data for estrogenic activity—Proof of concept

2015 ◽  
Vol 71 (3) ◽  
pp. 398-408 ◽  
Author(s):  
Richard A. Becker ◽  
Katie Paul Friedman ◽  
Ted W. Simon ◽  
M. Sue Marty ◽  
Grace Patlewicz ◽  
...  
Keyword(s):  
High Throughput ◽  
High Throughput Screening ◽  
Estrogenic Activity ◽  
Proof Of Concept

scholarly journals Common features of antibacterial compounds: an analysis of 10000 compounds library

2015 ◽  
Vol 61 (6) ◽  
pp. 785-790 ◽  
Author(s):  
M.S. Veselov ◽  
P.V. Sergiev ◽  
I.A. Osterman ◽  
D.A. Skvortsov ◽  
A.Ya. Golovina ◽  
...  
Keyword(s):  
Escherichia Coli ◽  
Antibacterial Activity ◽  
Organic Compounds ◽  
High Throughput ◽  
High Throughput Screening ◽  
Chemical Space ◽  
Molecular Target ◽  
Antibacterial Compounds ◽  
Common Features ◽  
Automated Screening

Antibacterial compounds are one of the essential classes of clinically important drugs. High throughput screening allowed revealing potential antibiotics active towards any molecular target in bacterial cell. We used a library of 9820 organic compounds with highly diversified structures to screen for antibacterial activity. As the result of automated screening, 103 compounds were found to possess antibacterial activity against Escherichia coli. The properties of these compounds were compared with those of initial library. Non-linear Kohonen mapping was used to analyze the differences between non-active molecules from initial library, identified antibacterial hits and compounds with reported antibacterial activity. It was found that identified antibacterial compounds are located in the separated area of chemical space. It can be therefore suggested that these molecules belong to novel classes of antibacterial compounds and could be studied further.

scholarly journals A Simple, No-Wash Cell Adhesion–Based High-Throughput Assay for the Discovery of Small-Molecule Regulators of the Integrin CD11b/CD18

2007 ◽  
Vol 12 (3) ◽  
pp. 406-417 ◽  
Author(s):  
Jun Y. Park ◽  
M. Amin Arnaout ◽  
Vineet Gupta
Keyword(s):  
High Throughput ◽  
High Throughput Screening ◽  
Biological Function ◽  
Inflammatory Diseases ◽  
Adhesion Assay ◽  
Proof Of Concept ◽  
Agonist And Antagonist ◽  
Blocking Antibodies ◽  
Affinity Interaction ◽  
High Throughput Assay

The leukocyte-specific integrin CD11b/CD18 plays a key role in the biological function of these cells and represents a validated therapeutic target for inflammatory diseases. Currently, the low affinity interaction between CD11b/CD18 integrin and its respective ligand poses a challenge in the development of cell-based adhesion assays for the high-throughput screening (HTS) environment. Here the authors describe a simple cell-based adhesion assay that can be readily used for HTS for the discovery of functional regulators of CD11b/CD18. The assay consistently produces acceptable Z' values (> 0.5) for HTS. After testing the assay using 2 established blocking antibodies as reference biologicals, the authors performed a proof-of-concept primary screen using a library of 6612 compounds and identified both agonist and antagonist hits. ( Journal of Biomolecular Screening 2007:406-417)

scholarly journals Cross-platform Bayesian optimization system for autonomous biological assay development

2021 ◽  
Author(s):  
Sam Elder ◽  
Carleen Klumpp-Thomas ◽  
Adam Yasgar ◽  
Jameson Travers ◽  
Shayne Frebert ◽  
...  
Keyword(s):  
High Throughput ◽  
High Throughput Screening ◽  
Assay Development ◽  
Bayesian Optimization ◽  
Biological Assay ◽  
Proof Of Concept ◽  
Screening Assay ◽  
High Throughput Screening Assay ◽  
Cross Platform ◽  
Assay Conditions

Current high-throughput screening assay optimization is often a manual and time-consuming process, even when utilizing design-of-experiment approaches. A cross-platform, Cloud-based Bayesian optimization-based algorithm was developed as part of the NCATS ASPIRE Initiative to accelerate preclinical drug discovery. A cell-free assay for papain enzymatic activity was used as proof-of-concept for biological assay development. Compared to a brute force approach that sequentially tested all 294 assay conditions to find the global optimum, the Bayesian optimization algorithm could find suitable conditions for optimal assay performance by testing only 21 assay conditions on average, with up to 20 conditions being tested simultaneously. The algorithm could achieve a seven-fold reduction in costs for lab supplies and high-throughput experimentation run-time, all while being controlled from a remote site through a secure connection. Based on this proof-of-concept, this technology is expected to be applied to more complex biological assays and automated chemistry reaction screening at NCATS, and should be transferable to other institutions.

scholarly journals Discovery of a Novel and Potent Class of FabI-Directed Antibacterial Agents

2002 ◽  
Vol 46 (10) ◽  
pp. 3118-3124 ◽  
Author(s):  
David J. Payne ◽  
William H. Miller ◽  
Valerie Berry ◽  
John Brosky ◽  
Walter J. Burgess ◽  
...  
Keyword(s):  
Antibacterial Activity ◽  
High Throughput ◽  
High Throughput Screening ◽  
Antibacterial Agents ◽  
Fatty Acid Biosynthesis ◽  
Acyl Carrier Protein ◽  
Multidrug Resistant ◽  
Infection Model ◽  
Enoyl Acp Reductase

ABSTRACT Bacterial enoyl-acyl carrier protein (ACP) reductase (FabI) catalyzes the final step in each elongation cycle of bacterial fatty acid biosynthesis and is an attractive target for the development of new antibacterial agents. High-throughput screening of the Staphylococcus aureus FabI enzyme identified a novel, weak inhibitor with no detectable antibacterial activity against S. aureus. Iterative medicinal chemistry and X-ray crystal structure-based design led to the identification of compound 4 [(E)-N-methyl-N-(2-methyl-1H-indol-3-ylmethyl)-3-(7-oxo-5,6,7,8-tetrahydro-1,8-naphthyridin-3-yl)acrylamide], which is 350-fold more potent than the original lead compound obtained by high-throughput screening in the FabI inhibition assay. Compound 4 has exquisite antistaphylococci activity, achieving MICs at which 90% of isolates are inhibited more than 500 times lower than those of nine currently available antibiotics against a panel of multidrug-resistant strains of S. aureus and Staphylococcus epidermidis. Furthermore, compound 4 exhibits excellent in vivo efficacy in an S. aureus infection model in rats. Biochemical and genetic approaches have confirmed that the mode of antibacterial action of compound 4 and related compounds is via inhibition of FabI. Compound 4 also exhibits weak FabK inhibitory activity, which may explain its antibacterial activity against Streptococcus pneumoniae and Enterococcus faecalis, which depend on FabK and both FabK and FabI, respectively, for their enoyl-ACP reductase function. These results show that compound 4 is representative of a new, totally synthetic series of antibacterial agents that has the potential to provide novel alternatives for the treatment of S. aureus infections that are resistant to our present armory of antibiotics.

scholarly journals AG205, a Novel Agent Directed against FabK of Streptococcus pneumoniae

2006 ◽  
Vol 50 (8) ◽  
pp. 2869-2871 ◽  
Author(s):  
Sho Takahata ◽  
Maiko Iida ◽  
Yumi Osaki ◽  
Jun Saito ◽  
Hideo Kitagawa ◽  
...  
Keyword(s):  
Antibacterial Activity ◽  
Streptococcus Pneumoniae ◽  
High Throughput ◽  
High Throughput Screening ◽  
Potent Inhibitor ◽  
Lipid Biosynthesis ◽  
Specific Inhibition ◽  
Enoyl Acp Reductase ◽  
Resistant Mutants ◽  
Novel Agent

ABSTRACT AG205 was identified from high-throughput screening as a potent inhibitor of FabK, the enoyl-ACP reductase in Streptococcus pneumoniae. Specific inhibition of lipid biosynthesis in a macromolecular biosynthesis assay and identification of an Ala141Ser substitution in FabK from spontaneous AG205-resistant mutants indicated that AG205 exerts antibacterial activity against S. pneumoniae through the specific inhibition of FabK.

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