scholarly journals De Novo Design of Type II Topoisomerase Inhibitors as Potential Antimicrobial Agents Targeting a Novel Binding Region

2021 ◽  
Author(s):  
Kyle Orritt ◽  
Juliette Newell ◽  
Lipeng Feng ◽  
Thomas Germe ◽  
Lauren Abbott ◽  
...  
Keyword(s):  
Binding Site ◽  
Antimicrobial Agents ◽  
De Novo ◽  
Molecular Design ◽  
Dna Gyrase ◽  
Fluoroquinolone Resistance ◽  
Allosteric Site ◽  
Ic50 Values ◽  
Antibacterial Target

By 2050 it is predicted that antimicrobial resistance will be responsible for 10 million global deaths annually, costing the world economy $100 trillion. Clearly, strategies to address this problem are required as bacterial evolution is rendering our current antibiotics ineffective. The discovery of an allosteric binding site on the established antibacterial target DNA gyrase offers a new medicinal chemistry strategy, as this site is distinct from the fluoroquinolone-DNA site binding site. Using in silico molecular design methods, we have designed and synthesised a novel series of biphenyl-based inhibitors inspired by the published thiophene allosteric inhibitor. This series was evaluated in vitro against E. coli DNA gyrase, exhibiting IC50 values in the low micromolar range. The structure-activity relationship reported herein suggests insights to further exploit this allosteric site, offering a pathway to overcome fluoroquinolone resistance.

scholarly journals In Vitro Characterization of the Antibacterial Spectrum of Novel Bacterial Type II Topoisomerase Inhibitors of the Aminobenzimidazole Class

2006 ◽  
Vol 50 (4) ◽  
pp. 1228-1237 ◽  
Author(s):  
Nagraj Mani ◽  
Christian H. Gross ◽  
Jonathan D. Parsons ◽  
Brian Hanzelka ◽  
Ute Müh ◽  
...  
Keyword(s):  
Bacterial Resistance ◽  
Wide Spectrum ◽  
Dna Gyrase ◽  
Antibacterial Activities ◽  
Mechanisms Of Action ◽  
Fluoroquinolone Resistance ◽  
Topoisomerase Iv ◽  
Low Frequencies

ABSTRACT Antibiotics with novel mechanisms of action are becoming increasingly important in the battle against bacterial resistance to all currently used classes of antibiotics. Bacterial DNA gyrase and topoisomerase IV (topoIV) are the familiar targets of fluoroquinolone and coumarin antibiotics. Here we present the characterization of two members of a new class of synthetic bacterial topoII ATPase inhibitors: VRT-125853 and VRT-752586. These aminobenzimidazole compounds were potent inhibitors of both DNA gyrase and topoIV and had excellent antibacterial activities against a wide spectrum of problematic pathogens responsible for both nosocomial and community-acquired infections, including staphylococci, streptococci, enterococci, and mycobacteria. Consistent with the novelty of their structures and mechanisms of action, antibacterial potency was unaffected by commonly encountered resistance phenotypes, including fluoroquinolone resistance. In time-kill assays, VRT-125853 and VRT-752586 were bactericidal against Staphylococcus aureus, Streptococcus pneumoniae, Enterococcus faecalis, and Haemophilus influenzae, causing 3-log reductions in viable cells within 24 h. Finally, similar to the fluoroquinolones, relatively low frequencies of spontaneous resistance to VRT-125853 and VRT-752586 were found, a property consistent with their in vitro dual-targeting activities.

Experimental and theoretical investigation of new 1,3,4-oxadiazole based dioxovanadium (VO+2) complexes and their in-vitro antimicrobial potency

2021 ◽  
Vol 11 (6) ◽  
pp. 888-903
Author(s):  
Hanan Alghamdi ◽  
Syed Nazreen ◽  
Ahmed A. Elhenawy ◽  
Mohamed Abdelbaset
Keyword(s):  
Thermal Analysis ◽  
Antimicrobial Activity ◽  
Biological System ◽  
Antimicrobial Agents ◽  
Dna Gyrase ◽  
Fungal Strain ◽  
Interaction Mode ◽  
Vanadium Ions ◽  
Antimicrobial Potency

The antimicrobial resistance is a global human threat which has led to the withdrawal of antibiotics from the market. Therefore, it is a need to develop new and effective antimicrobial agents to overcome this problem. In this paper, new Dioxovanadium(V) complexes (1–8) with ligands viz. (2-(5-phenyl-1,3,4-oxadiazole-2-yl)phenol; L1) and 2,5-bis(2-hydroxyphenyl)-1,3,4-oxadiazole (L2) were synthesized and assessed for antimicrobial-activity. Both a bidentate and tetradentate oxadiazole ligands coordinate with vanadium ions through the nitrogen and oxygen atoms giving octahedral geometries. Thermal analysis and IR data confirmed the presence of hydrated water in the metal-complexes. The investigated compounds were assessed for antimicrobial viz four strains of bacterial and one a fungal strain. The antibacterial data showed that, the complexes (1–8) are lower potency against bacterial strain than the free ligands except (5) and (7) complexes. These complexness showed the highest antibacterial potency via the Staphylococcus aureus. All investigated compounds were inactive against C. albicans except complexes 2 and 5 which showed high activity. The performance of DFT was conducted to examine an interaction mode of the target compounds with biological system. The QSPR was calculated as: optimization geometries, (FMOs), and chemical-reactivities for the synthesized compounds. The (MEPs) were figured to predict the interaction behavior of the ligand and its complexes against the receptor. The molecular docking was performed against DNA gyrase to study the interaction mode with biological system.

scholarly journals Derivatization of Rosmarinic Acid Enhances its in vitro Antitumor, Antimicrobial and Antiprotozoal Properties

Molecules ◽  
2019 ◽  
Vol 24 (6) ◽  
pp. 1078 ◽  
Author(s):  
Silvia Bittner Fialová ◽  
Martin Kello ◽  
Matúš Čoma ◽  
Lívia Slobodníková ◽  
Eva Drobná ◽  
...  
Keyword(s):  
Rosmarinic Acid ◽  
Antimicrobial Agents ◽  
Biological Activities ◽  
Fold Increase ◽  
Inhibitory Effect ◽  
Phosphonium Salts ◽  
Ros Scavenging ◽  
Ic50 Values ◽  
Quaternary Phosphonium Salts

On its own, rosmarinic acid possesses multiple biological activities such as anti-inflammatory, antimicrobial, cardioprotective and antitumor properties, and these are the consequence of its ROS scavenging and inhibitory effect on inflammation. In this study, two quaternary phosphonium salts of rosmarinic acid were prepared for the purpose of increasing its penetration into biological systems with the aim of improving its antimicrobial, antifungal, antiprotozoal and antitumor activity. The synthetized molecules, the triphenylphosphonium and tricyclohexylphosphonium salts of rosmarinic acid, exhibited significantly stronger inhibitory effects on the growth of HCT116 cells with IC50 values of 7.28 or 8.13 μM in comparison to the initial substance, rosmarinic acid (>300 μM). For the synthesized derivatives, we detected a greater than three-fold increase of activity against Acanthamoeba quina, and a greater than eight-fold increase of activity against A. lugdunensis in comparison to rosmarinic acid. Furthermore, we recorded significantly higher antimicrobial activity of the synthetized derivatives when compared to rosmarinic acid itself. Both synthetized quaternary phosphonium salts of rosmarinic acid appear to be promising antitumor and antimicrobial agents, as well as impressive molecules for further research.

scholarly journals Synthesis, Antimicrobial Activity and Molecular Docking of Novel Thiourea Derivatives Tagged with Thiadiazole, Imidazole and Triazine Moieties as Potential DNA Gyrase and Topoisomerase IV Inhibitors

Molecules ◽  
2020 ◽  
Vol 25 (12) ◽  
pp. 2766 ◽  
Author(s):  
Heba E. Hashem ◽  
Abd El-Galil E. Amr ◽  
Eman S. Nossier ◽  
Elsayed A. Elsayed ◽  
Eman M. Azmy
Keyword(s):  
Antimicrobial Activity ◽  
Molecular Docking ◽  
Antimicrobial Agents ◽  
Biological Activities ◽  
Topoisomerase Iv ◽  
Thiourea Derivatives ◽  
E Coli ◽  
Cytotoxicity Studies ◽  
Ic50 Values

To develop new antimicrobial agents, a series of novel thiourea derivatives incorporated with different moieties 2–13 was designed and synthesized and their biological activities were evaluated. Compounds 7a, 7b and 8 exhibited excellent antimicrobial activity against all Gram-positive and Gram-negative bacteria, and the fungal Aspergillus flavus with minimum inhibitory concentration (MIC) values ranged from 0.95 ± 0.22 to 3.25 ± 1.00 μg/mL. Furthermore, cytotoxicity studies against MCF-7 cells revealed that compounds 7a and 7b were the most potent with IC50 values of 10.17 ± 0.65 and 11.59 ± 0.59 μM, respectively. On the other hand, the tested compounds were less toxic against normal kidney epithelial cell lines (Vero cells). The in vitro enzyme inhibition assay of 8 displayed excellent inhibitory activity against Escherichia coli DNA B gyrase and moderate one against E. coli Topoisomerase IV (IC50 = 0.33 ± 1.25 and 19.72 ± 1.00 µM, respectively) in comparison with novobiocin (IC50 values 0.28 ± 1.45 and 10.65 ± 1.02 µM, respectively). Finally, the molecular docking was done to position compound 8 into the E. coli DNA B and Topoisomerase IV active pockets to explore the probable binding conformation. In summary, compound 8 may serve as a potential dual E. coli DNA B and Topoisomerase IV inhibitor.

scholarly journals Combining Generative Artificial Intelligence and On-Chip Synthesis for De Novo Drug Design

2020 ◽  
Author(s):  
Francesca Grisoni ◽  
Berend Huisman ◽  
Alexander Button ◽  
Michael Moret ◽  
Kenneth Atz ◽  
...  
Keyword(s):  
Artificial Intelligence ◽  
Drug Design ◽  
De Novo ◽  
Molecular Design ◽  
Chemical Space ◽  
Amide Bond ◽  
Reaction Products ◽  
De Novo Drug Design ◽  
On Chip

<p>Automation of the molecular design-make-test-analyze cycle speeds up the identification of hit and lead compounds for drug discovery. Using deep learning for computational molecular design and a customized microfluidics platform for on-chip compound synthesis, liver X receptor (LXR) agonists were generated from scratch. The computational pipeline was tuned to explore the chemical space defined by known LXRα agonists, and to suggest structural analogs of known ligands and novel molecular cores. To further the design of lead-like molecules and ensure compatibility with automated on-chip synthesis, this chemical space was confined to the set of virtual products obtainable from 17 different one-step reactions. Overall, 25 <i>de novo</i> generated compounds were successfully synthesized in flow via formation of sulfonamide, amide bond, and ester bond. First-pass <i>in vitro</i> activity screening of the crude reaction products in hybrid Gal4 reporter gene assays revealed 17 (68%) hits, with up to 60-fold LXR activation. The batch re-synthesis, purification, and re-testing of 14 of these compounds confirmed that 12 of them were potent LXRα or LXRβ agonists. These results support the utilization of the proposed design-make-test-analyze framework as a blueprint for automated drug design with artificial intelligence and miniaturized bench-top synthesis.<b></b></p>

scholarly journals Genetic Analyses of Mutations Contributing to Fluoroquinolone Resistance in Clinical Isolates ofStreptococcus pneumoniae

2001 ◽  
Vol 45 (12) ◽  
pp. 3517-3523 ◽  
Author(s):  
L. M. Weigel ◽  
G. J. Anderson ◽  
R. R. Facklam ◽  
F. C. Tenover
Keyword(s):  
Amino Acid ◽  
Antimicrobial Agents ◽  
Clinical Isolates ◽  
Fluoroquinolone Resistance ◽  
Cross Resistance ◽  
Genetic Analyses ◽  
High Level ◽  
Susceptibility Profiles ◽  
Level Resistance

ABSTRACT Twenty-one clinical isolates of Streptococcus pneumoniae showing reduced susceptibility or resistance to fluoroquinolones were characterized by serotype, antimicrobial susceptibility, and genetic analyses of the quinolone resistance-determining regions (QRDRs) of gyrA,gyrB, parC, and parE. Five strains were resistant to three or more classes of antimicrobial agents. In susceptibility profiles for gatifloxacin, gemifloxacin, levofloxacin, moxifloxacin, ofloxacin, sparfloxacin, and trovafloxacin, 14 isolates had intermediate- or high-level resistance to all fluoroquinolones tested except gemifloxacin (no breakpoints assigned). Fluoroquinolone resistance was not associated with serotype or with resistance to other antimicrobial agents. Mutations in the QRDRs of these isolates were more heterogeneous than those previously reported for mutants selected in vitro. Eight isolates had amino acid changes at sites other than ParC/S79 and GyrA/S81; several strains contained mutations in gyrB, parE, or both loci. Contributions to fluoroquinolone resistance by individual amino acid changes, including GyrB/E474K, ParE/E474K, and ParC/A63T, were confirmed by genetic transformation of S. pneumoniae R6. Mutations in gyrB were important for resistance to gatifloxacin but not moxifloxacin, and mutation of gyrAwas associated with resistance to moxifloxacin but not gatifloxacin, suggesting differences in the drug-target interactions of the two 8-methoxyquinolones. The positions of amino acid changes within the four genes affected resistance more than did the total number of QRDR mutations. However, the effect of a specific mutation varied significantly depending on the agent tested. These data suggest that the heterogeneity of mutations will likely increase as pneumococci are exposed to novel fluoroquinolone structures, complicating the prediction of cross-resistance within this class of antimicrobial agents.

scholarly journals Design, Synthesis, and Antibacterial Screening of Some Novel Heteroaryl-Based Ciprofloxacin Derivatives as DNA Gyrase and Topoisomerase IV Inhibitors

2021 ◽  
Vol 14 (5) ◽  
pp. 399
Author(s):  
Lamya H. Al-Wahaibi ◽  
Amer A. Amer ◽  
Adel A. Marzouk ◽  
Hesham A.M. Gomaa ◽  
Bahaa G. M. Youssif ◽  
...  
Keyword(s):  
Antibacterial Activity ◽  
Dna Gyrase ◽  
Bacterial Strains ◽  
Topoisomerase Iv ◽  
Gram Positive ◽  
Gram Negative ◽  
E Coli ◽  
Antibacterial Screening ◽  
Ic50 Values

A novel series of ciprofloxacin hybrids comprising various heterocycle derivatives has been synthesized and structurally elucidated using 1H NMR, 13C NMR, and elementary analyses. Using ciprofloxacin as a reference, compounds 1–21 were screened in vitro against Gram-positive bacterial strains such as Staphylococcus aureus and Bacillus subtilis and Gram-negative strains such as Escherichia coli and Pseudomonas aeruginosa. As a result, many of the compounds examined had antibacterial activity equivalent to ciprofloxacin against test bacteria. Compounds 2–6, oxadiazole derivatives, were found to have antibacterial activity that was 88 to 120% that of ciprofloxacin against Gram-positive and Gram-negative bacteria. The findings showed that none of the compounds tested had antifungal activity against Aspergillus flavus, but did have poor activity against Candida albicans, ranging from 23% to 33% of fluconazole, with compound 3 being the most active (33% of fluconazole). The most potent compounds, 3, 4, 5, and 6, displayed an IC50 of 86, 42, 92, and 180 nM against E. coli DNA gyrase, respectively (novobiocin, IC50 = 170 nM). Compounds 4, 5, and 6 showed IC50 values (1.47, 6.80, and 8.92 µM, respectively) against E. coli topo IV in comparison to novobiocin (IC50 = 11 µM).

scholarly journals The Evolution of Fluoroquinolone Resistance in Salmonella under Exposure to Sub-Inhibitory Concentration of Enrofloxacin

2021 ◽  
Vol 22 (22) ◽  
pp. 12218
Author(s):  
Yufeng Gu ◽  
Lulu Huang ◽  
Cuirong Wu ◽  
Junhong Huang ◽  
Haihong Hao ◽  
...  
Keyword(s):  
De Novo ◽  
Efflux Pump ◽  
Decisive Role ◽  
Resistance Rate ◽  
Fluoroquinolone Resistance ◽  
Salmonella Enterica Serovar Enteritidis ◽  
Resistance Level ◽  
Resistance Evolution ◽  
Selection Of

The evolution of resistance in Salmonella to fluoroquinolones (FQs) under a broad range of sub-inhibitory concentrations (sub-MICs) has not been systematically studied. This study investigated the mechanism of resistance development in Salmonella enterica serovar Enteritidis (S. Enteritidis) under sub-MICs of 1/128×MIC to 1/2×MIC of enrofloxacin (ENR), a widely used veterinary FQ. It was shown that the resistance rate and resistance level of S. Enteritidis varied with the increase in ENR concentration and duration of selection. qRT-PCR results demonstrated that the expression of outer membrane porin (OMP) genes, ompC, ompD and ompF, were down-regulated first to rapidly adapt and develop the resistance of 4×MIC, and as the resistance level increased (≥8×MIC), the up-regulated expression of efflux pump genes, acrB, emrB amd mdfA, along with mutations in quinolone resistance-determining region (QRDR) gradually played a decisive role. Cytohubba analysis based on transcriptomic profiles demonstrated that purB, purC, purD, purF, purH, purK, purL, purM, purN and purT were the hub genes for the FQs resistance. The ‘de novo’ IMP biosynthetic process, purine ribonucleoside monophosphate biosynthetic process and purine ribonucleotide biosynthetic process were the top three biological processes screened by MCODE. This study first described the dynamics of FQ resistance evolution in Salmonella under a long-term selection of sub-MICs of ENR in vitro. In addition, this work offers greater insight into the transcriptome changes of S. Enteritidis under the selection of ENR and provides a framework for FQs resistance of Salmonella for further studies.

scholarly journals Combining generative artificial intelligence and on-chip synthesis for de novo drug design

2021 ◽  
Vol 7 (24) ◽  
pp. eabg3338
Author(s):  
Francesca Grisoni ◽  
Berend J. H. Huisman ◽  
Alexander L. Button ◽  
Michael Moret ◽  
Kenneth Atz ◽  
...  
Keyword(s):  
Artificial Intelligence ◽  
Drug Design ◽  
De Novo ◽  
Molecular Design ◽  
Chemical Space ◽  
Reaction Products ◽  
De Novo Drug Design ◽  
On Chip ◽  
Lxr Agonists

Automating the molecular design-make-test-analyze cycle accelerates hit and lead finding for drug discovery. Using deep learning for molecular design and a microfluidics platform for on-chip chemical synthesis, liver X receptor (LXR) agonists were generated from scratch. The computational pipeline was tuned to explore the chemical space of known LXRα agonists and generate novel molecular candidates. To ensure compatibility with automated on-chip synthesis, the chemical space was confined to the virtual products obtainable from 17 one-step reactions. Twenty-five de novo designs were successfully synthesized in flow. In vitro screening of the crude reaction products revealed 17 (68%) hits, with up to 60-fold LXR activation. The batch resynthesis, purification, and retesting of 14 of these compounds confirmed that 12 of them were potent LXR agonists. These results support the suitability of the proposed design-make-test-analyze framework as a blueprint for automated drug design with artificial intelligence and miniaturized bench-top synthesis.

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