Targeting Bacterial Sortase A with Covalent Inhibitors: 27 New Starting Points for Structure-Based Hit-to-Lead Optimization

Jaudzems, Kristaps; Kurbatska, Viktorija; Kabsons, Atis Je; Bobrovs, Raitis; Rudevica, Zhanna; Leonchiks, Ainars

doi:10.1021/acsinfecdis.9b00265

Cited by 31 publications

(33 citation statements)

References 36 publications

(73 reference statements)

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“…Previous research campaigns investigated competitive‐reversible S. aureus SrtA inhibitors including promising scaffolds such as 2‐morpholinobenzoates, thiadiazoles, 2‐phenylthiazoles, macrocyclic peptides, 2‐phenylbenzoxazoles, and various other inhibitors . 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 .…”

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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“…In addition, the IC 50 value of orientin against S. aureus SrtA in vitro was significantly lower than that of natural product inhibitors reported previously, such as quercetin, kaempferol, galangin, and isorhamnetin [9], which means that orientin may be more effective in inhibiting SrtA. In addition, inhibitors of SrtA can be categorized as either covalent or non-covalent [58,59]. If there is a choice, drug developers prefer non-covalent inhibitors to covalent modify enzyme inhibitors, which overcome the drawbacks of covalent inhibitors, such as high toxicity, nonrecoverability, non-repairability, and other side effects [60].…”

Section: Discussionmentioning

confidence: 65%

Orientin mediates protection against MRSA-induced pneumonia by inhibiting Sortase A

Wang

Jing

et al. 2021

Virulence

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Drug-resistant pathogenic Staphylococcus aureus (S. aureus) has severely threatened human health and arouses widespread concern. Sortase A (SrtA) is an essential virulence factor of S. aureus, which is responsible for the covalent anchoring of a variety of virulence-related proteins to the cell wall. SrtA has always been regarded as an ideal pharmacological target against S. aureus infections. In this research, we have determined that orientin, a natural compound isolated from various medicinal plants, can effectively inhibit the activity of SrtA with an IC 50 of 50.44 ± 0.51 µM. We further demonstrated that orientin inhibited the binding of S. aureus to fibrinogen and diminished biofilm formation and the attaching of Staphylococcal protein A (SpA) to the cell wall in vitro. Using the fluorescence quenching assay, we demonstrated a direct interaction between orientin and SrtA. Further mechanistic studies revealed that the residues Glu-105, Thr-93, and Cys-184 were the key sites for the binding of SrtA to orientin. Importantly, we demonstrated that treatment with orientin attenuated S. aureus virulence of in vivo and protected mice against S. aureus-induced lethal pneumonia. These findings indicate that orientin is a potential drug to counter S. aureus infections and limit the development of drug resistance.

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“…We identified the natural compound Tax that could block SrtA activity, with an IC 50 of 24.53 ± 0.42 μM. Inhibitors of SrtA can be categorized as either covalent or non-covalent ( Jackson et al, 2017 ; Jaudzems et al, 2020 ). The formation of covalent bonds occurs via the reaction of an inhibitor with the cysteine active site ( Hou et al, 2018 ; Barthels et al, 2020 ).…”

Section: Discussionmentioning

confidence: 99%

Taxifolin, an Inhibitor of Sortase A, Interferes With the Adhesion of Methicillin-Resistant Staphylococcal aureus

Wang

et al. 2021

Front. Microbiol.

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The evolution and spread of methicillin-resistant Staphylococcus aureus (MRSA) poses a significant hidden risk to human public health. The majority of antibiotics used clinically have become mostly ineffective, and so the development of novel anti-infection strategies is urgently required. Since Staphylococcus aureus (S. aureus) cysteine transpeptidase sortase A (SrtA) mediates the surface-anchoring of proteins to its surface, compounds that inhibit SrtA are considered potential antivirulence treatments. Herein, we report on the efficacy of the potent SrtA inhibitor taxifolin (Tax), a flavonoid compound isolated from Chinese herbs. It was able to reversibly block the activity of SrtA with an IC50 of 24.53 ± 0.42 μM. Tax did not display toxicity toward mammalian cells or S. aureus at a concentration of 200 μM. In addition, Tax attenuated the virulence-related phenotype of SrtA in vitro by decreasing the adherence of S. aureus, reducing the formation of a biofilm, and anchoring of S. aureus protein A on its cell wall. The mechanism of the SrtA-Tax interaction was determined using a localized surface plasmon resonance assay. Subsequent mechanistic studies confirmed that Asp-170 and Gln-172 were the principal sites on SrtA with which it binds to Tax. Importantly, in vivo experiments demonstrated that Tax protects mice against pneumonia induced by lethal doses of MRSA, significantly improving their survival rate and reducing the number of viable S. aureus in the lung tissue. The present study indicates that Tax is a useful pioneer compound for the development of novel agents against S. aureus infections.

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Targeting Bacterial Sortase A with Covalent Inhibitors: 27 New Starting Points for Structure-Based Hit-to-Lead Optimization

Cited by 31 publications

References 36 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

Orientin mediates protection against MRSA-induced pneumonia by inhibiting Sortase A

Taxifolin, an Inhibitor of Sortase A, Interferes With the Adhesion of Methicillin-Resistant Staphylococcal aureus

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