Sulfonylpiperidines as novel, antibacterial inhibitors of Gram-positive thymidylate kinase (TMK)

Martínez-Botella, Gabriel; Loch, James T.; Green, Oluyinka M.; Kawatkar, Sameer; Olivier, N.B.; Boriack-Sjodin, P.A.; Keating, Thomas A.

doi:10.1016/j.bmcl.2012.10.128

Cited by 24 publications

(19 citation statements)

References 7 publications

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“…FERONIA was required for cell elongation during vegetative growth [ 50 ], suggesting that the genes in subgroup III might play an important role in plant morphology. In subgroup IV, TMK1 was an essential enzyme for DNA synthesis in bacteria [ 51 ], which indicated that the genes of subgroup IV might play a critical role in cell expansion and proliferation regulation. The subgroup V gene RLK1 was reported to increase tolerance to salinity, heavy metal stresses, and Botrytis cinerea infection [ 52 ], suggesting that the genes of subgroup V are implicated in biotic and abiotic stress responses.…”

Section: Discussionmentioning

confidence: 99%

Genome-wide identification and evolutionary analysis of RLKs involved in the response to aluminium stress in peanut

Wang

Xiao

et al. 2021

BMC Plant Biol

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Background As an important cash crop, the yield of peanut is influenced by soil acidification and pathogen infection. Receptor-like protein kinases play important roles in plant growth, development and stress responses. However, little is known about the number, location, structure, molecular phylogeny, and expression of RLKs in peanut, and no comprehensive analysis of RLKs in the Al stress response in peanuts have been reported. Results A total of 1311 AhRLKs were identified from the peanut genome. The AhLRR-RLKs and AhLecRLKs were further divided into 24 and 35 subfamilies, respectively. The AhRLKs were randomly distributed across all 20 chromosomes in the peanut. Among these AhRLKs, 9.53% and 61.78% originated from tandem duplications and segmental duplications, respectively. The ka/ks ratios of 96.97% (96/99) of tandem duplication gene pairs and 98.78% (646/654) of segmental duplication gene pairs were less than 1. Among the tested tandem duplication clusters, there were 28 gene conversion events. Moreover, all total of 90 Al-responsive AhRLKs were identified by mining transcriptome data, and they were divided into 7 groups. Most of the Al-responsive AhRLKs that clustered together had similar motifs and evolutionarily conserved structures. The gene expression patterns of these genes in different tissues were further analysed, and tissue-specifically expressed genes, including 14 root-specific Al-responsive AhRLKs were found. In addition, all 90 Al-responsive AhRLKs which were distributed unevenly in the subfamilies of AhRLKs, showed different expression patterns between the two peanut varieties (Al-sensitive and Al-tolerant) under Al stress. Conclusions In this study, we analysed the RLK gene family in the peanut genome. Segmental duplication events were the main driving force for AhRLK evolution, and most AhRLKs subject to purifying selection. A total of 90 genes were identified as Al-responsive AhRLKs, and the classification, conserved motifs, structures, tissue expression patterns and predicted functions of Al-responsive AhRLKs were further analysed and discussed, revealing their putative roles. This study provides a better understanding of the structures and functions of AhRLKs and Al-responsive AhRLKs.

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Section: Discussionmentioning

confidence: 99%

Genome-wide identification and evolutionary analysis of RLKs involved in the response to aluminium stress in peanut

Wang

Xiao

et al. 2021

BMC Plant Biol

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“…Martínez-Botella et al (2012) also reported the positions of the Tmk piperidinylthymine binding site. Furthermore, we found that Keating et al (2012) reported that piperidinylthymines exhibited activity in an in vivo mouse model of S. aureus MRSA252 infection and that Martínez-Botella et al (2013) reported that piperidinylthymines are moderately and weakly active against gramnegative and human Tmk, respectively. This analysis suggests that piperidinylthymines are good potential lead anti-Mycoplasma compounds.…”

Section: Literature Search For Lead Inhibitor Compoundsmentioning

confidence: 94%

“…We examined the seven piperidinylthymine compounds with experimentally determined structures contained within the PDB ligand database (Shin and Cho, 2005) which also have low reported S. aureus 50% inhibitory concentrations (IC 50 ). We curated IC 50 values from Martínez-Botella et al (2012), Keating et al (2012), Martínez-Botella et al (2013), and Kawatkar et al (2014). Table 2 lists the predicted interaction energies of each of the seven compounds with M. genitalium, S. aureus, and H. sapiens Tmk.…”

Section: Structural Analysis Of Binding Site Conservation and Energeticsmentioning

confidence: 99%

A combined systems and structural modeling approach repositions antibiotics for Mycoplasma genitalium

Kazakiewicz

Karr

Langner

et al. 2015

Computational Biology and Chemistry

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“…3). The screen identified known inhibitors of DNA metabolism that were present in the compound library, such as quinolones (9) and other inhibitors of DNA gyrase (GyrA) (39), as well as ATPase inhibitors of GyrB (40)(41)(42)(43), DNA ligase (44,45), and thymidylate kinase (46,47). Given that the assay identified a wide variety of inhibitors, rather than inhibitors of just a single target, the assay was validated as a useful probe to identify inhibitors of DNA metabolism (Fig.…”

Section: Resultsmentioning

confidence: 99%

A Novel High-Throughput Cell-Based Assay Aimed at Identifying Inhibitors of DNA Metabolism in Bacteria

Fan

Jonge

MacCormack

et al. 2014

Antimicrob Agents Chemother

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cBacterial biosensor strains can be useful tools for the discovery and characterization of antibacterial compounds. A plasmid-based reporter vector containing a transcriptional fusion between the recA promoter and green fluorescence protein gene was introduced into an Escherichia coli ⌬tolC strain to create a biosensor strain that selectively senses inhibitors of DNA metabolism via the SOS response. The strain was used to develop a high-throughput assay to identify new inhibitors of DNA metabolism. Screening of the AstraZeneca compound library with this strain identified known inhibitors of DNA metabolism, as well as novel chemotypes. The cellular target of one novel series was elucidated as DNA gyrase through genetic characterization of laboratory-generated resistant mutants followed by 50% inhibitory concentration measurements in a DNA gyrase activity assay. These studies validated the use of this antibiotic biosensor strain to identify novel selective inhibitors of DNA metabolism by high-throughput screening.

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Sulfonylpiperidines as novel, antibacterial inhibitors of Gram-positive thymidylate kinase (TMK)

Cited by 24 publications

References 7 publications

Genome-wide identification and evolutionary analysis of RLKs involved in the response to aluminium stress in peanut

Genome-wide identification and evolutionary analysis of RLKs involved in the response to aluminium stress in peanut

A combined systems and structural modeling approach repositions antibiotics for Mycoplasma genitalium

A Novel High-Throughput Cell-Based Assay Aimed at Identifying Inhibitors of DNA Metabolism in Bacteria

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