Novel inhibitors of the methicillin-resistant <i>Staphylococcus aureus</i> (MRSA)-pyruvate kinase

Sayed, Mardia T. El; Zoraghi, Roya; Reiner, Neil E.; Süzen, Síbel; Ohlsen, Knut; Lalk, Michael; Altanlar, Nurten; Hilgeroth, Andreas

doi:10.3109/14756366.2015.1118685

Cited by 15 publications

(14 citation statements)

References 18 publications

(17 reference statements)

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“…PK has recently been discovered as an essential hub-protein in the interactome of MRSA [21]. The PK inhibitory activity of the tested compounds was determined according to the previously reported method [22]. Shortly, MRSA PK was expressed in pET-28a (+) as a recombinant protein in E. coli BL-21(DE3) and then purified by using Ni-nitrilotriacetic acid (NTA) agarose (Quiagen, Inc., Germantown, MD).…”

Section: In Vitro Enzymes Assaymentioning

confidence: 99%

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Discovery of Two Brominated Oxindole Alkaloids as Staphylococcal DNA Gyrase and Pyruvate Kinase Inhibitors via Inverse Virtual Screening

et al. 2020

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In the present study, a small marine-derived natural products library was assessed for antibacterial potential. Among 36 isolated compounds, a number of bis-indole derivatives exhibited growth-inhibitory activity towards Gram-positive strains (Bacillus subtilis and multidrug-resistant Staphylococcus aureus). 5- and 6-trisindoline (5-Tris and 6-Tris) were the most active derivatives (minimum inhibitory concentration, MIC, 4–8 µM) that were subsequently selected for anti-biofilm activity evaluation. Only 5-Tris was able to inhibit the staphylococcal biofilm formation starting at a 5 µM concentration. In order to investigate their possible molecular targets, both natural products were subjected to in silico inverse virtual screening. Among 20 target proteins, DNA gyrase and pyruvate kinase were the most likely to be involved in the observed antibacterial and anti-biofilm activities of both selected natural products. The in vitro validation and in silico binding mode studies revealed that 5-Tris could act as a dual enzyme inhibitor (IC50 11.4 ± 0.03 and 6.6 ± 0.05 µM, respectively), while 6-Tris was a low micromolar gyrase-B inhibitor (IC50 2.1 ± 0.08 µM), indicating that the bromine position plays a crucial role in the determination of the antibacterial lead compound inhibitory activity.

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Section: In Vitro Enzymes Assaymentioning

confidence: 99%

“…To further evaluate the anti-biofilm activity of 5-Tris and 6-Tris in Gram-positive bacteria, they were tested at different concentrations against the reference strain S. epidermidis RP62A [2,22]. As shown in Figure 3, both molecules reduced the growth of an S. epidermidis standard strain in a dose-dependent manner.…”

Section: Antibiofilm Activitymentioning

confidence: 99%

Discovery of Two Brominated Oxindole Alkaloids as Staphylococcal DNA Gyrase and Pyruvate Kinase Inhibitors via Inverse Virtual Screening

et al. 2020

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“…The mechanistic study revealed that these three dimers (IC 50 : 6.1–8.5 µM) could exhibit the anti‐MRSA activity through the inhibition of MRSA PK. [ 51 ]…”

Section: Indole Dimersmentioning

confidence: 99%

“…The mechanistic study revealed that these three dimers (IC 50 : 6.1-8.5 µM) could exhibit the anti-MRSA activity through the inhibition of MRSA PK. [51] The anti-MRSA SAR of indole-oxindole heteronuclear dimer 26 and the introduction of the electron-donating group at the C-5 position decreased the activity. [52,53] It was observed that dimers 26a,b (MIC: , and VRE strains.…”

Section: F I G U R E 3 Chemical Structures Of Indole Dimers 13-22mentioning

confidence: 99%

Recent advances in indole dimers and hybrids with antibacterial activity against methicillin‐resistant Staphylococcus aureus

Meng

Hou

Shang

et al. 2020

Archiv der Pharmazie

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Methicillin‐resistant Staphylococcus aureus (MRSA), one of the major and most dangerous pathogens in humans, is a causative agent of severe pandemic of mainly skin and soft tissue and occasionally fatal infections. Therefore, it is imperative to develop potent and novel anti‐MRSA agents. Indole derivatives could act against diverse enzymes and receptors in bacteria, occupying a salient place in the development of novel antibacterial agents. Dimerization and hybridization are common strategies to discover new drugs, and a number of indole dimers and hybrids possess potential antibacterial activity against a panel of clinically important pathogens including MRSA. Accordingly, indole dimers and hybrids are privileged scaffolds for the discovery of novel anti‐MRSA agents. This review outlines the recent development of indole dimers and hybrids with a potential activity against MRSA, covering articles published between 2010 and 2020. The structure–activity relationship and the mechanism of action are also discussed to facilitate further rational design of more effective candidates.

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“…The increasing resistance to available antibiotics against clinically important bacteria represents a serious problem in public health which increases the need of development of new therapeutic alternatives. Among the various antibacterial infections, the Gram positive S. aureus infections remain one of the most challenging due to the increasing resistance, particularly the methicillin‐resistant S. aurues (MRSA) strains . Many later reports presented new heterocyclic compounds with promising anti MRSA activities.…”

Section: Introductionmentioning

confidence: 99%

Novel Pyruvate Kinase (PK) Inhibitors: New Target to Overcome Bacterial Resistance

et al. 2020

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In the present investigation, some novel nitro Mannich bases derived from Michael type addition of activated nitro olefin, β‐nitrostyrene with various amines either primary or secondary including some amino sugars were designed and synthesized. The produced Mannich bases have been full characterized through different spectroscopic techniques. Antimicrobial evaluation has been performed against the Gram positive S. aureus and methicillin‐resistant S. aurues (MRSA) infections. 5 of the synthesized compounds represent the best candidates in the biological screening, they have exhibited good activity with MIC values range from 100 to 250 μg/ml. The active agents have been tested for pyruvate kinase inhibition activity with % of inhibition range from 30 to 79 % with IC50 in a nano molar range. They also exhibited significant Pyruvate kinase inhibition in nanomolar range with IC50 of 1066, 662, 1887, 418 and 1128 ng/ml, respectively (versus 196 ng/ml for AZD7545). Molecular docking calculations for active agents were performed. A complete conformational analysis molecular modeling utilizing Gaussian 09 program (HF/DFT) was used to verify the mode of bonding through the optimized geometries as well as essential quantum parameters were calculated using frontier energies (EHOMO & ELUMO) for the active candidates indicating the overall stability of the structure.

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Novel inhibitors of the methicillin-resistant Staphylococcus aureus (MRSA)-pyruvate kinase

Cited by 15 publications

References 18 publications

Discovery of Two Brominated Oxindole Alkaloids as Staphylococcal DNA Gyrase and Pyruvate Kinase Inhibitors via Inverse Virtual Screening

Discovery of Two Brominated Oxindole Alkaloids as Staphylococcal DNA Gyrase and Pyruvate Kinase Inhibitors via Inverse Virtual Screening

Recent advances in indole dimers and hybrids with antibacterial activity against methicillin‐resistant Staphylococcus aureus

Novel Pyruvate Kinase (PK) Inhibitors: New Target to Overcome Bacterial Resistance

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