Screening of compound library identifies novel inhibitors against the MurA enzyme of Escherichia coli

Raina, Diksha; Tiwari, Harshita; Sharma, Smriti; Deepika,; Chinthakindi, Praveen K.; Nargotra, Amit; Sangwan, Payare L.; Eniyan, Kandasamy; Bajpai, Urmi; Vishwakarma, Ram A.; Khan, Farrah; Saran, Saurabh; Khan, Inshad Ali

doi:10.1007/s00253-021-11272-4

Cited by 8 publications

(5 citation statements)

References 52 publications

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“…This statement is not only sustained by literature data [ 25 , 33 ], but also by the absence of Michael acceptors in the chemical structure of the diterpenes which are necessary for covalent interactions with Cys115. The binding of the active compounds to Arg120 and Arg91 is of great importance due to the key role of these amino acids in stabilizing the closed conformation of the enzyme through interaction with the phosphonate group of UDP-GlcNAc [ 9 , 34 ]. One of the mechanisms of fosfomycin resistance is the mutation of Cys115 to Asp, which rendered bacteria completely insensitive to the antibiotic [ 35 ].…”

Section: Discussionmentioning

confidence: 99%

Inhibition of MurA Enzyme from Escherichia coli and Staphylococcus aureus by Diterpenes from Lepechinia meyenii and Their Synthetic Analogs

et al. 2021

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Enzymes MurA and MurF, involved in bacterial cell wall synthesis, have been validated as targets for the discovery of novel antibiotics. A panel of plant-origin antibacterial diterpenes and synthetic analogs derived therefrom were investigated for their inhibitory properties on these enzymes from Escherichia coli and Staphylococcus aureus. Six compounds were proven to be effective for inhibiting MurA from both bacteria, with IC50 values ranging from 1.1 to 25.1 µM. To further mechanistically investigate the nature of binding and to explain the activity, these compounds were docked into the active site of MurA from E. coli. The aromatic ring of the active compounds showed a T-shaped π–π interaction with the phenyl ring of Phe328, and at least one hydrogen bond was formed between the hydroxy groups and Arg120 and/or Arg91. The results disclosed here establish new chemical scaffolds for the development of novel entities targeting MurA as potential antibiotics to combat the threat of pathogenic bacteria, particularly resistant strains.

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Section: Discussionmentioning

confidence: 99%

Inhibition of MurA Enzyme from Escherichia coli and Staphylococcus aureus by Diterpenes from Lepechinia meyenii and Their Synthetic Analogs

et al. 2021

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“…Through macromolecular labeling, it has been found that the above inhibitors do not promote the uptake of propidium iodide, thus the antibacterial effect may not be related to the cell damage (Silver, 2013). In recent years, more MurA inhibitors, including IN00152, IN00156, allylpyrocatechol derivatives, and heterocyclic electrophiles, have been discovered (Keeley et al, 2018;Kurnia et al, 2020;Raina et al, 2021), which highlighted the involvement of computer simulation and screening in future research. Among these, IN00152, IN00156, and allylpyrocatechol derivatives can non-competitively inhibit substrates UDP-GlcNAc and PEP, and the effectiveness increases along with the substrate concentrations (Kurnia et al, 2020;Raina et al, 2021).…”

Section: Muramentioning

confidence: 99%

“…In recent years, more MurA inhibitors, including IN00152, IN00156, allylpyrocatechol derivatives, and heterocyclic electrophiles, have been discovered (Keeley et al, 2018;Kurnia et al, 2020;Raina et al, 2021), which highlighted the involvement of computer simulation and screening in future research. Among these, IN00152, IN00156, and allylpyrocatechol derivatives can non-competitively inhibit substrates UDP-GlcNAc and PEP, and the effectiveness increases along with the substrate concentrations (Kurnia et al, 2020;Raina et al, 2021). Furthermore, by combining IN00152 and IN00156 with antibiotics (carbenicillin, ciprofloxacin, gentamicin, and tetracycline), the additive interaction between them has been elucidated (Raina et al, 2021).…”

Section: Muramentioning

confidence: 99%

“…Among these, IN00152, IN00156, and allylpyrocatechol derivatives can non-competitively inhibit substrates UDP-GlcNAc and PEP, and the effectiveness increases along with the substrate concentrations (Kurnia et al, 2020;Raina et al, 2021). Furthermore, by combining IN00152 and IN00156 with antibiotics (carbenicillin, ciprofloxacin, gentamicin, and tetracycline), the additive interaction between them has been elucidated (Raina et al, 2021).…”

Section: Muramentioning

confidence: 99%

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Breaking down the cell wall: Still an attractive antibacterial strategy

et al. 2022

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Since the advent of penicillin, humans have known about and explored the phenomenon of bacterial inhibition via antibiotics. However, with changes in the global environment and the abuse of antibiotics, resistance mechanisms have been selected in bacteria, presenting huge threats and challenges to the global medical and health system. Thus, the study and development of new antimicrobials is of unprecedented urgency and difficulty. Bacteria surround themselves with a cell wall to maintain cell rigidity and protect against environmental insults. Humans have taken advantage of antibiotics to target the bacterial cell wall, yielding some of the most widely used antibiotics to date. The cell wall is essential for bacterial growth and virulence but is absent from humans, remaining a high-priority target for antibiotic screening throughout the antibiotic era. Here, we review the extensively studied targets, i.e., MurA, MurB, MurC, MurD, MurE, MurF, Alr, Ddl, MurI, MurG, lipid A, and BamA in the cell wall, starting from the very beginning to the latest developments to elucidate antimicrobial screening. Furthermore, recent advances, including MraY and MsbA in peptidoglycan and lipopolysaccharide, and tagO, LtaS, LspA, Lgt, Lnt, Tol-Pal, MntC, and OspA in teichoic acid and lipoprotein, have also been profoundly discussed. The review further highlights that the application of new methods such as macromolecular labeling, compound libraries construction, and structure-based drug design will inspire researchers to screen ideal antibiotics.

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“…Enzymes are common targets in high-throughput screening ( 21 ). Additionally, the repurposing of existing drugs already approved by the Food and Drug Administration (FDA) for human therapy is regarded as an effective strategy for drug development ( 22 ).…”

Section: Introductionmentioning

confidence: 99%

Canagliflozin, characterized as a HDAC6 inhibitor, inhibits gastric cancer metastasis

Jiang

2022

Front. Oncol.

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Gastric cancer is a common gastrointestinal cancer. Survival outcome for patients with the recurrence or metastasis remains poor due to the lack of effective targeting drugs. The mechanisms of non-histone acetylation modifications are key epigenetic regulations that participate in various biological processes. HDAC6 is mostly located in the cytoplasm to deacetylate non-histone substrates, which has been identified as a critical promoter of many oncogenic pathways in cancers, including gastric cancer. Nevertheless, its inhibitor has not been applied in gastric cancer clinically. In this study, we identified canagliflozin as an active HDAC6-targeted inhibitor from FDA-approved Drug Library by enzymatic assay. The strong affinity of the compounds with HDAC6 was further verified by surface plasmon resonance (SPR) and cellular thermal shift assay (CETSA). In addition, molecular docking showed that canagliflozin could bind to the active pocket of HDAC6 and form interactions with key residues. Further experiments revealed that canagliflozin could effectively inhibit the migration and epithelial-mesenchymal-transition (EMT) of gastric cancer cells in vitro and in vivo. These results reveal a novel finding that canagliflozin has the potential to be an effective agent in inhibiting gastric cancer metastasis.

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Screening of compound library identifies novel inhibitors against the MurA enzyme of Escherichia coli

Cited by 8 publications

References 52 publications

Inhibition of MurA Enzyme from Escherichia coli and Staphylococcus aureus by Diterpenes from Lepechinia meyenii and Their Synthetic Analogs

Inhibition of MurA Enzyme from Escherichia coli and Staphylococcus aureus by Diterpenes from Lepechinia meyenii and Their Synthetic Analogs

Breaking down the cell wall: Still an attractive antibacterial strategy

Canagliflozin, characterized as a HDAC6 inhibitor, inhibits gastric cancer metastasis

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