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

Nițulescu, George Mihai; Mihai, Dragoș Paul; Nicorescu, I.; Olaru, Octavian Tudorel; Ungurianu, Anca; Zanfirescu, Anca; Margină, Denisa

doi:10.1002/ddr.21599

Cited by 28 publications

(31 citation statements)

References 42 publications

(50 reference statements)

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“…However, the most active compounds were found to be irreversible covalent inhibitors containing an electrophilic warhead that reacts with the active‐site Cys126 of SrtA . While having significant inhibition in the low micromolar range, they typically exhibit poor target selectivity or are cytotoxic such as quinones, rhodanines, or benzisothiazolinones . Zhulenkovs et al .…”

Section: Introductionmentioning

confidence: 99%

Asymmetric Disulfanylbenzamides as Irreversible and Selective Inhibitors of Staphylococcus aureus Sortase A

et al. 2020

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Staphylococcus aureus is one of the most frequent causes of nosocomial and community-acquired infections, with drugresistant strains being responsible for tens of thousands of deaths per year. S. aureus sortase A inhibitors are designed to interfere with virulence determinants. We have identified disulfanylbenzamides as a new class of potent inhibitors against sortase A that act by covalent modification of the active-site cysteine. A broad series of derivatives were synthesized to derive structure-activity relationships (SAR). In vitro and in silico methods allowed the experimentally observed binding affinities and selectivities to be rationalized. The most active compounds were found to have single-digit micromolar K i values and caused up to a 66 % reduction of S. aureus fibrinogen attachment at an effective inhibitor concentration of 10 μM. This new molecule class exhibited minimal cytotoxicity, low bacterial growth inhibition and impaired sortase-mediated adherence of S. aureus cells. a 100 % � 0.5 % 93 % � 5.6 % n.i. 7 a 98 % � 0.1 % 14 % � 8.9 % 18 % � 1.1 % 7 f 60 % � 0.5 % n.i. 12 % � 3.1 % 7 g 18 % � 3.9 % n.i. 17 % � 7.7 % 7 h 69 % � 1.7 % 23 % � 11 % 13 % � 8.0 % 12 a 90 % � 0.5 % n.i. 15 % � 5.7 % n.i. = no inhibition at 20 μM compound concentration. All results include the mean value and standard deviations from triplicate measurements.

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Section: Introductionmentioning

confidence: 99%

Asymmetric Disulfanylbenzamides as Irreversible and Selective Inhibitors of Staphylococcus aureus Sortase A

et al. 2020

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“…Prior to the determination, young daphnids were selected according to their size and maintained for 24 h in artificial medium. The bioassay was performed on 10 daphnids/replicates in tissue culture plates with 12 wells (Greiner Bio-One) according to the protocol described in our previous studies [ 50 , 51 ]. For each compound, six concentrations were tested, ranging from 5 to 128 µM.…”

Section: Methodsmentioning

confidence: 99%

Synthesis and Anticancer Evaluation of New 1,3,4-Oxadiazole Derivatives

et al. 2021

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In order to develop novel chemotherapeutic agents with potent anticancer activities, a series of new 2,5-diaryl/heteroaryl-1,3,4-oxadiazoles were designed and synthesized. The structures of the new compounds were established using elemental analyses, IR and NMR spectral data. The compounds were evaluated for their anticancer potential on two standardized human cell lines, HT-29 (colon adenocarcinoma) and MDA-MB-231 (breast adenocarcinoma). Cytotoxicity was measured by MTS assay, while cell cycle arrest and apoptosis assays were conducted using a flow cytometer, the results showing that the cell line MDA-MB-231 is more sensitive to the compounds’ action. The results of the predictive studies using the PASS application and the structural similarity analysis indicated STAT3 and miR-21 as the most probable pharmacological targets for the new compounds. The promising effect of compound 3e, 2-[2-(phenylsulfanylmethyl)phenyl]-5-(4-pyridyl)-1,3,4-oxadiazole, especially on the MDA-MB-231 cell line motivates future studies to improve the anticancer profile and to reduce the toxicological risks. It is worth noting that 3e produced a low toxic effect in the D. magna 24 h assay and the predictive studies on rat acute toxicity suggest a low degree of toxic risks.

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“…The inhibition kinetics and docking studies indicated an irreversible mechanism based on the Cys184’s thiol catalytic residue addition to the dual conjugated double system of the naphthoquinone structure. Lawsone, the 2-hydroxy-isomer of juglone, had no significant effect on Sa-SrtA at 10 μM because of its low reactivity towards nucleophilic agents [ 68 ]. The chemical structures of these naphthoquinone derivatives are presented in Figure 6 .…”

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

Cited by 28 publications

References 42 publications

Asymmetric Disulfanylbenzamides as Irreversible and Selective Inhibitors of Staphylococcus aureus Sortase A

Asymmetric Disulfanylbenzamides as Irreversible and Selective Inhibitors of Staphylococcus aureus Sortase A

Synthesis and Anticancer Evaluation of New 1,3,4-Oxadiazole Derivatives

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

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