Novel Sortase A Inhibitors to Counteract Gram-Positive Bacterial Biofilms

Raimondi, Maria Valeria; Listro, Roberta; Cusimano, Maria Grazia; Franca, Mery La; Faddetta, Teresa; Gallo, Giuseppe; Schillaci, Domenico; Collina, Simona; Leonchiks, Ainars; Barone, Giampaolo

doi:10.3390/proceedings2019022023

Cited by 5 publications

(5 citation statements)

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“…The inhibition of SrtA is related to the attenuation of virulence in Staphylococcus aureus and also in other important Gram-positive pathogens as Listeria monocytogenes , Streptococcus pneumoniae , and Streptococcus mutans [ [47] , [48] , [49] , [50] ]. With the aim to investigate the mechanism of action of pyrrolomycins [ [51] , [52] , [53] , [54] , [55] , [57] , [58] ], in 2019, Raimondi et al. [ 59 ] prepared six pyrrolomycins via microwave-assisted synthesis.…”

Section: Antimicrobial Activitymentioning

confidence: 99%

Bioactive pyrrole-based compounds with target selectivity

Petri

Spanò

Spatola

et al. 2020

European Journal of Medicinal Chemistry

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141

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The discovery of novel synthetic compounds with drug-like properties is an ongoing challenge in medicinal chemistry. Natural products have inspired the synthesis of compounds for pharmaceutical application, most of which are based on N -heterocyclic motifs. Among these, the pyrrole ring is one of the most explored heterocycles in drug discovery programs for several therapeutic areas, confirmed by the high number of pyrrole-based drugs reaching the market. In the present review, we focused on pyrrole and its hetero-fused derivatives with anticancer, antimicrobial, and antiviral activities, reported in the literature between 2015 and 2019, for which a specific target was identified, being responsible for their biological activity. It emerges that the powerful pharmaceutical and pharmacological features provided by the pyrrole nucleus as pharmacophore unit of many drugs are still recognized by medicinal chemists.

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Section: Antimicrobial Activitymentioning

confidence: 99%

Bioactive pyrrole-based compounds with target selectivity

Petri

Spanò

Spatola

et al. 2020

European Journal of Medicinal Chemistry

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141

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“…Also, ageliferin (Ⅲ) is a natural pyrrole-containing derivative secreted by sponges with potent antibacterial properties (Bhardwaj et al, 2015;Ma et al, 2015). Raimondi et al (2019) synthesized a series of pyrrolomycin derivatives, from which compound Ⅳ showed high efficiency against Staphylococcus aureus inhibiting SrtA enzyme (Li Petri et al, 2020). In addition, compounds Ⅴ and Ⅵ are examples of sulfonamide-containing pyrrole characterized by remarkable antifungal activities compared to mycostatin (El-Gaby et al, 2002;Kaur et al, 2017).…”

Section: Introductionmentioning

confidence: 99%

New pyrrole derivatives as DNA gyrase and 14α‐demethylase inhibitors: Design, synthesis, antimicrobial evaluation, and molecular docking

Hilmy,

Kishk,

Shahen

et al. 2023

Drug Development Research

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An efficient one‐pot reaction utilizing readily available chemical reagents was used to prepare novel 2‐amino‐1,5‐diaryl‐1H‐pyrrole‐3‐carbonitrile derivatives and the structures of these compounds were validated by spectroscopic data and elemental analyses. All the synthetic compounds were evaluated for their antimicrobial activities (MZI assay). The tested compounds proved high activities on Staphylococcus aureus (Gram‐positive bacteria) and Candida albicans (Pathogenic fungi). However, they did not show any activity on Escherichia coli (Gram‐negative bacteria). The most effective compounds in MZI assay 7c, 9a, 9b, 11a, and 11b were selected to determine their MIC on S. aureus and C. albicans. Furthermore, DNA gyrase and 14‐α demethylase inhibitory assays were performed to study the inhibitory activities of 7c, 9a, 9b, 11a, and 11b. The results illustrated that compound 9b was the most DNA gyrase inhibitor (IC50 of 0.0236 ± 0.45 µM, which was 1.3‐ fold higher than gentamicin reference IC50 values of 0.0323 ± 0.81 µM). In addition, compound 9b demonstrated the highest 14‐α demethylase inhibitory effect with IC50 of 0.0013 ± 0.02 µM, compared to ketoconazole (IC50 of 0.0008 ± 0.03 µM) and fluconazole (IC50 of 0.00073 ± 0.01 µM), as antifungal reference drugs. Lastly, docking studies were performed to rationalize the dual inhibitory activities of the highly active compounds on both DNA gyrase and 14‐α demethylase enzymes.

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“…This enzyme speeds up two consecutive reactions: (a) transpeptidation and (b) thioesterification. SrtA is involved in the bacterial adhesion process and acts by attaching proteins holding LPXTG to lipid II [1][2][3][4][5][6][7][8][9][10][11]. SrtA inhibitors do not influence bacterial growth, but instead, they prevent the emergence of the virulence of pathogenic bacterial strains, thereby hindering infections produced by Staphylococcus aureus (S. aureus) or other bacteria of Gram-positive strain.…”

Section: Introductionmentioning

confidence: 99%

3D-QSAR Studies of 1,2,4-Oxadiazole Derivatives as Sortase A Inhibitors

Shakour

Hadizadeh

Kesharwani

et al. 2021

BioMed Research International

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Sortase A (SrtA) is an enzyme that catalyzes the attachment of proteins to the cell wall of Gram-positive bacterial membrane, preventing the spread of pathogenic bacterial strains. Here, one class of oxadiazole compounds was distinguished as an efficient inhibitor of SrtA via the “S. aureus Sortase A” substrate-based virtual screening. The current study on 3D-QSAR was done by utilizing preparation of the structure in the Schrödinger software suite and an assessment of 120 derivatives with the crystal structure of 1,2,4-oxadiazole which was extracted from the PDB data bank. The docking operation of the best compound in terms of pMIC ( pMIC = 2.77 ) was done to determine the drug likeliness and binding form of 1,2,4-oxadiazole derivatives as antibiotics in the active site. Using the kNN-MFA way, seven models of 3D-QSAR were created and amongst them, and one model was selected as the best. The chosen model based on q 2 (pred_ r 2 ) and R 2 values related to the sixth factor of PLS illustrates better and more acceptable external and internal predictions. Values of crossvalidation (pred_ r 2 ), validation ( q 2 ), and F were observed 0.5479, 0.6319, and 179.0, respectively, for a test group including 24 molecules and the training group including 96 molecules. The external reliability outcomes showed that the acceptable and the selective 3D-QSAR model had a high predictive potential ( R 2 = 0.9235 ) which was confirmed by the Y -randomization test. Besides, the model applicability domain was described successfully to validate the estimation of the model.

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Novel Sortase A Inhibitors to Counteract Gram-Positive Bacterial Biofilms

Abstract: Sortase A (SrtA) is a membrane enzyme responsible for the covalent anchoring of surface proteins on the cell wall of Gram-positive bacteria. [...]

Cited by 5 publications

References 4 publications

Bioactive pyrrole-based compounds with target selectivity

Bioactive pyrrole-based compounds with target selectivity

New pyrrole derivatives as DNA gyrase and 14α‐demethylase inhibitors: Design, synthesis, antimicrobial evaluation, and molecular docking

3D-QSAR Studies of 1,2,4-Oxadiazole Derivatives as Sortase A Inhibitors

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