Sortase A (SrtA) is a membrane enzyme responsible for the covalent anchoring of surface proteins on the cell wall of Gram-positive bacteria. Nowadays it is considered an interesting target for the development of new anti-infective drugs which aim to interfere with important Gram-positive virulence mechanisms. Along the years, we studied the anti-staphylococcal and anti-biofilm activity of some natural and synthetic polyhalogenated pyrrolic compounds, called pyrrolomycins. Some of them were active on Gram-positive pathogens at a μg/mL range of concentration (1.5-0.045 μg/mL) and showed a biofilm inhibition in the range of 50-80%. [1-3] In light of these encouraging results, herein we present our efforts in the design and synthesis of novel pyrrolomycins. To dispose of sufficient amount for the in-depth in vitro investigation, we developed an efficient and easy-to-use microwave synthetic methodology. All compounds showed a good inhibitory activity toward SrtA, in accordance with the molecular modelling studies, having IC50 values ranging from 130 to 300 µM comparable to berberine hydrochloride, our reference compound. Particularly, the pentabromo-derivative exhibited the highest capability to interfere with biofilm formation of S. aureus with an IC50 of 3.4 nM. This compound was also effective in altering S. aureus murein hydrolase activity, responsible for degradation, turnover, and maturation of bacterial peptidoglycan and involved in the initial stages of S. aureus biofilm formation. [4]

Maria Valeria Raimondi, R.L. (2019). Novel Sortase A Inhibitors to Counteract Gram-Positive Bacterial Biofilms. PROCEEDINGS, 22(1), 1-2 [10.3390/proceedings2019022023].

Novel Sortase A Inhibitors to Counteract Gram-Positive Bacterial Biofilms

Maria Valeria Raimondi
;
Maria Grazia Cusimano;Mery La Franca;Teresa Faddetta;Giuseppe Gallo;Domenico Schillaci;Giampaolo Barone
2019-08-07

Abstract

Sortase A (SrtA) is a membrane enzyme responsible for the covalent anchoring of surface proteins on the cell wall of Gram-positive bacteria. Nowadays it is considered an interesting target for the development of new anti-infective drugs which aim to interfere with important Gram-positive virulence mechanisms. Along the years, we studied the anti-staphylococcal and anti-biofilm activity of some natural and synthetic polyhalogenated pyrrolic compounds, called pyrrolomycins. Some of them were active on Gram-positive pathogens at a μg/mL range of concentration (1.5-0.045 μg/mL) and showed a biofilm inhibition in the range of 50-80%. [1-3] In light of these encouraging results, herein we present our efforts in the design and synthesis of novel pyrrolomycins. To dispose of sufficient amount for the in-depth in vitro investigation, we developed an efficient and easy-to-use microwave synthetic methodology. All compounds showed a good inhibitory activity toward SrtA, in accordance with the molecular modelling studies, having IC50 values ranging from 130 to 300 µM comparable to berberine hydrochloride, our reference compound. Particularly, the pentabromo-derivative exhibited the highest capability to interfere with biofilm formation of S. aureus with an IC50 of 3.4 nM. This compound was also effective in altering S. aureus murein hydrolase activity, responsible for degradation, turnover, and maturation of bacterial peptidoglycan and involved in the initial stages of S. aureus biofilm formation. [4]
7-ago-2019
The 2nd Molecules Medicinal Chemistry Symposium (MMCS): Facing Novel Challenges in Drug Discovery)
Barcellona
15-17/05/2019
Maria Valeria Raimondi, R.L. (2019). Novel Sortase A Inhibitors to Counteract Gram-Positive Bacterial Biofilms. PROCEEDINGS, 22(1), 1-2 [10.3390/proceedings2019022023].
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/10447/356330
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