Quinone skeleton as a new class of irreversible inhibitors against Staphylococcus aureus sortase A

Hou, Xiaochen; Wang, Meining; Wen, Yi; Ni, Tengfeng; Guan, Xiang-Na; Lan, Lefu; Zhang, Naixia; Zhang, Ao; Yang, Cai‐Guang

doi:10.1016/j.bmcl.2018.04.005

Cited by 25 publications

(24 citation statements)

References 39 publications

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“…The data indicates a higher reactivity towards nucleophilic agents for juglone and plumbagin and supports the hypothesis of a thiol nucleophilic attack, explaining the lack of effect on SaSrtA for lawsone. After this research was performed a recent article (Hou et al, ) describes compounds with a quinone skeleton as irreversible inhibitors covalently binding the active Cys184 residue supporting our results.…”

Section: Resultssupporting

confidence: 80%

Discovery of natural naphthoquinones as sortase A inhibitors and potential anti‐infective solutions against Staphylococcus aureus

Nițulescu

Mihai

Nicorescu

et al. 2019

Drug Development Research

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Three natural naphthoquinones were screened to find new anti‐virulence agents as inhibitors against sortase A from Staphylococcus aureus (SaSrtA) by quantifying the increase in fluorescence intensity upon substrate cleavage at various concentrations. The 5‐hydroxy‐1,4‐naphthalenedione derivatives, juglone and plumbagin, demonstrated a potent inhibitory effect, with IC50 values of 1.78 μM, respectively, 16.71 μM. The related 2‐hydroxy‐1,4‐naphthalenedione derivative, lawsone, demonstrated the selectivity of the chemical scaffold having no significant effect on SaSrtA. The experimental assay was reinforced by molecular docking experiments, antimicrobial, and toxicological studies. Molecular docking studies and the electrophilic character analysis suggest bonding to the enzyme active cysteine residue by a Michael addition reaction. None of the compounds had a significant effect on the concentration of total thiol proteins in the Daphnia magna toxicological assay after 24 hr exposure. Juglone and plumbagin moderately inhibited biofilm formation with no significant effect on bacterial growth of S. aureus, Enterococcus faecalis, and Staphylococcus epidermidis, indicating a selective anti‐virulence profile.

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Section: Resultssupporting

confidence: 80%

Discovery of natural naphthoquinones as sortase A inhibitors and potential anti‐infective solutions against Staphylococcus aureus

Nițulescu

Mihai

Nicorescu

et al. 2019

Drug Development Research

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“…A screening for SrtA inhibitors using a clinical drug and a natural product-based library and the monitoring of SrtAΔ24 cleavage of Abz-LPETG-Dnp substrate, identified two natural 5,8-dihydroxy-1,4-naphthoquinone derivatives, shikonin (IC 50 = 0.30 μM) and alkannin (IC 50 = 0.36 μM). The compounds are enantiomers and they both strongly inhibit the growth and viability of S. aureus [ 67 ] limiting considerably their use as anti-virulence agents. Similar 1,4-naphthoquinone derivatives, juglone (5-hydroxy-1,4-naphthalenedione) and its 2-methyl analogue, plumbagin, demonstrated a potent Sa-SrtA inhibitory effect with IC 50 values of 1.78 µM and 16.71 µM respectively, without significantly influencing the bacterial growth of S. aureus , E. faecalis , and S. epidermidis .…”

Section: Sortase a Inhibitorsmentioning

confidence: 99%

“…The two derivatives ( Figure 6 ) are diastereomers differing in the stereochemistry of just one carbon atom, the isomer R being more active towards Sa-SrtA. Both compounds significantly attenuated the biofilm production at 80 μM and had no impact on the growth of S. aureus at 150 μM, demonstrating a good anti-virulence profile [ 67 ].…”

Section: Sortase a Inhibitorsmentioning

confidence: 99%

Targeting Bacterial Sortases in Search of Anti-virulence Therapies with Low Risk of Resistance Development

et al. 2021

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Increasingly ineffective antibiotics and rapid spread of multi- and pan-resistant bacteria represent a global health threat; hence, the need of developing new antimicrobial medicines. A first step in this direction is identifying new molecular targets, such as virulence factors. Sortase A represents a virulence factor essential for the pathogenesis of Gram-positive pathogens, some of which have a high risk for human health. We present here an exhaustive collection of sortases inhibitors grouped by relevant chemical features: vinyl sulfones, 3-aryl acrylic acids and derivatives, flavonoids, naphtoquinones, anthraquinones, indoles, pyrrolomycins, isoquinoline derivatives, aryl β-aminoethyl ketones, pyrazolethiones, pyridazinones, benzisothiazolinones, 2-phenyl-benzoxazole and 2-phenyl-benzofuran derivatives, thiadiazoles, triazolothiadiazoles, 2-(2-phenylhydrazinylidene)alkanoic acids, and 1,2,4-thiadiazolidine-3,5-dione. This review focuses on highlighting their structure–activity relationships, using the half maximal inhibitory concentration (IC50), when available, as an indicator of each compound effect on a specific sortase. The information herein is useful for acquiring knowledge on diverse natural and synthetic sortases inhibitors scaffolds and for understanding the way their structural variations impact IC50. It will hopefully be the inspiration for designing novel effective and safe sortase inhibitors in order to create new anti-infective compounds and to help overcoming the current worldwide antibiotic shortage.

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“…15 Further research revealed that loss of SrtA reduced biolm phenotype in S. aureus, 16 and inhibition of SrtA activity attenuated the biolm formation of S. aureus. 17 In addition, it was demonstrated that overexpression of SrtA resulted in increased levels of biolm formation in some staphylococcal strains. 18 Therefore, SrtA appears to be a promising target for identifying biolm inhibitors due to its important role in S. aureus biolm formation.…”

Section: Introductionmentioning

confidence: 99%

Inhibitory effect of a natural phenolic compound, 3-p-trans-coumaroyl-2-hydroxyquinic acid against the attachment phase of biofilm formation of Staphylococcus aureus through targeting sortase A

Liu

Bai

et al. 2019

RSC Adv.

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Quinone skeleton as a new class of irreversible inhibitors against Staphylococcus aureus sortase A

Cited by 25 publications

References 39 publications

Discovery of natural naphthoquinones as sortase A inhibitors and potential anti‐infective solutions against Staphylococcus aureus

Discovery of natural naphthoquinones as sortase A inhibitors and potential anti‐infective solutions against Staphylococcus aureus

Targeting Bacterial Sortases in Search of Anti-virulence Therapies with Low Risk of Resistance Development

Inhibitory effect of a natural phenolic compound, 3-p-trans-coumaroyl-2-hydroxyquinic acid against the attachment phase of biofilm formation of Staphylococcus aureus through targeting sortase A

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