Antibacterial small molecules targeting the conserved TOPRIM domain of DNA gyrase

Walker, Scott S.; Labroli, Marc; Painter, Ronald E.; Wiltsie, Judyann; Sherborne, Brad; Murgolo, Nicholas; Sher, Xinwei; Mann, Paul A.; Zuck, Paul; Garlisi, Charles G.; Su, Jing; Kargman, Stacia; Xiao, Li; Scapin, Giovanna; Salowe, Scott P.; Devito, Kristine; Sheth, Payal R.; Buist, Nichole; Tan, Christopher M.; Black, Todd A.; Roemer, Terry

doi:10.1371/journal.pone.0180965

Cited by 12 publications

(9 citation statements)

References 54 publications

(58 reference statements)

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…48 WG-3 activity was therefore tested in an E. coli strain with a mutation in the hotspot region of gyrase A (D87N) conferring resistance to quinolones. 49 A 4-fold decrease in WG-3 potency was seen in the GyrA mutant when compared to the WT strain (Figure S5), suggesting WG-3 acts at least in part via gyrase inhibition. These data suggest that WG-3 may be binding to both protein and structured RNA targets.…”

Section: ■ Results and Discussionmentioning

confidence: 98%

“…WG-3 is in the quinolone class of antibacterials that inhibit DNA gyrase and topoisomerase II or IV . WG-3 activity was therefore tested in an E. coli strain with a mutation in the hotspot region of gyrase A (D87N) conferring resistance to quinolones . A 4-fold decrease in WG-3 potency was seen in the GyrA mutant when compared to the WT strain (Figure S5), suggesting WG-3 acts at least in part via gyrase inhibition.…”

Section: Resultsmentioning

confidence: 99%

See 1 more Smart Citation

Discovery of Selective RNA-Binding Small Molecules by Affinity-Selection Mass Spectrometry

et al. 2018

Self Cite

View full text Add to dashboard Cite

Recent advances in understanding the relevance of noncoding RNA (ncRNA) to disease have increased interest in drugging ncRNA with small molecules. The recent discovery of ribocil, a structurally distinct synthetic mimic of the natural ligand of the flavin mononucleotide (FMN) riboswitch, has revealed the potential chemical diversity of small molecules that target ncRNA. Affinity-selection mass spectrometry (AS-MS) is theoretically applicable to high-throughput screening (HTS) of small molecules binding to ncRNA. Here, we report the first application of the Automated Ligand Detection System (ALIS), an indirect AS-MS technique, for the selective detection of small molecule-ncRNA interactions, high-throughput screening against large unbiased small-molecule libraries, and identification and characterization of novel compounds (structurally distinct from both FMN and ribocil) that target the FMN riboswitch. Crystal structures reveal that different compounds induce various conformations of the FMN riboswitch, leading to different activity profiles. Our findings validate the ALIS platform for HTS screening for RNA-binding small molecules and further demonstrate that ncRNA can be broadly targeted by chemically diverse yet selective small molecules as therapeutics.

show abstract

Section: ■ Results and Discussionmentioning

confidence: 98%

Section: Resultsmentioning

confidence: 99%

Discovery of Selective RNA-Binding Small Molecules by Affinity-Selection Mass Spectrometry

et al. 2018

Self Cite

View full text Add to dashboard Cite

show abstract

“…Inhibition of MtbTopI and DNA gyrase activity was evaluated with electrophoretic analysis [10,14–16]. Each reaction contained 1 U of enzyme, defined as the minimum amount required for complete conversion of the DNA substrate to product.…”

Section: Methodsmentioning

confidence: 99%

Mechanism and resistance for antimycobacterial activity of a fluoroquinophenoxazine compound

et al. 2019

View full text Add to dashboard Cite

We have previously reported the inhibition of bacterial topoisomerase I activity by a fluoroquinophenoxazine compound (FP-11g) with a 6-bipiperidinyl lipophilic side chain that exhibited promising antituberculosis activity (MIC = 2.5 μM against Mycobacterium tuberculosis , SI = 9.8). Here, we found that the compound is bactericidal towards Mycobacterium smegmatis , resulting in greater than 5 Log 10 reduction in colony-forming units [cfu]/mL following a 10 h incubation at 1.25 μM (4X MIC) concentration. Growth inhibition (MIC = 50 μM) and reduction in cfu could also be observed against a clinical isolate of Mycobacterium abscessus . Stepwise isolation of resistant mutants of M . smegmatis was conducted to explore the mechanism of resistance. Mutations in the resistant isolates were identified by direct comparison of whole-genome sequencing data from mutant and wild-type isolates. These include mutations in genes likely to affect the entry and retention of the compound. FP-11g inhibits Mtb topoisomerase I and Mtb gyrase with IC 50 of 0.24 and 27 μM, respectively. Biophysical analysis showed that FP-11g binds DNA as an intercalator but the IC 50 for inhibition of Mtb topoisomerase I activity is >10 fold lower than the compound concentrations required for producing negatively supercoiled DNA during ligation of nicked circular DNA. Thus, the DNA-binding property of FP-11g may contribute to its antimycobacterial mechanism, but that alone cannot account for the observed inhibition of M tb topoisomerase I.

show abstract

“…Fluoroquinolones and coumarin derivatives are potent antimicrobial agents which act by DNA Gyrase inhibition. DNA Gyrase with its subunits (2 Gyr A and 2 Gyr B) introduces negative supercoils in DNA and effectively inhibits initiation step of DNA synthesis [31]. Interestingly, several potent inhibitors such as novobiocin, clorobiocin, cyclothialidine, and 5ʹ-adenylyl-β,γ-imidodiphosphate (ATP analog) were found to interact with Asp-73, crucial amino acid present in the ATP binding domain of DNA Gyrase [32].…”

Section: Molecular Docking Studiesmentioning

confidence: 99%

Synthesis, in Silico Studies and Evaluation of Antibacterial Activity of 4-Substituted Benzylidene-2-(Phenoxymethyl) Oxazol-5(4h)-Ones

Begum¹,

Sk²,

Maneesha³

et al. 2019

Asian J Pharm Clin Res

View full text Add to dashboard Cite

Objective: Arylidene-1, 3-oxazol-5-ones represent potential antibacterial agents. In the present work, a series of 4-substituted benzylidene-2- (phenoxymethyl) oxazol-5(4H)-ones were synthesized and screened for antibacterial activity against Gram-negative bacteria Escherichia coli. To explore plausible mechanisms, synthesized compounds were docked with DNA-Gyrase enzyme. Methods: All the reactants, phenoxy acetyl chloride, acetic anhydride, sodium acetate, substituted aromatic aldehydes, and glycine were triturated in a mortar by mechanical stirring. The antibacterial potentiality of the compounds was screened against E. coli using the disk diffusion method and the activity was recorded as a zone of inhibition. Results: Compound 2d, possessing 3, 4, 5-trimethoxy functionality on benzylidene ring exhibited the highest activity with 19 mm of the zone of inhibition which might be due to its higher interactions with DNA-Gyrase enzyme (ΔG-8.41 kcal/mol). Compounds 2a, 2b, and 2c exhibited moderate activity in the antimicrobial assay as well as in docking study indicating the positive contribution of substitution on benzylidene ring. Conclusion: A series of 4-substituted benzylidene-2-(phenoxymethyl) oxazol-5(4H)-ones were synthesized and evaluated for antibacterial activity. Compounds 2a, 2b, and 2c displayed moderate activity whereas 2d showed maximum zone of inhibition (19 mm). The good activity of these derivatives presumed to be due to the conformational flexibility of phenoxy methylene moiety which can be well accommodated in the target binding site.

show abstract

Antibacterial small molecules targeting the conserved TOPRIM domain of DNA gyrase

Cited by 12 publications

References 54 publications

Discovery of Selective RNA-Binding Small Molecules by Affinity-Selection Mass Spectrometry

Discovery of Selective RNA-Binding Small Molecules by Affinity-Selection Mass Spectrometry

Mechanism and resistance for antimycobacterial activity of a fluoroquinophenoxazine compound

Synthesis, in Silico Studies and Evaluation of Antibacterial Activity of 4-Substituted Benzylidene-2-(Phenoxymethyl) Oxazol-5(4h)-Ones

Contact Info

Product

Resources

About