Novel Sortase A Inhibitors to Counteract Gram-Positive Bacterial Biofilms

Risultato della ricerca: Conference contribution

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]
Lingua originaleEnglish
Titolo della pubblicazione ospiteMMCS 2019 - FACING NOVEL CHALLENGES IN DRUG DISCOVERY - 2nd Molecules Medicinal Chemistry Symposium
Pagine209-209
Numero di pagine1
Stato di pubblicazionePublished - 2019

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Biofilms
N-Acetylmuramoyl-L-alanine Amidase
Berberine
Molecular modeling
Peptidoglycan
Pathogens
Bacteria
Membrane Proteins
Microwaves
Cells
Derivatives
Membranes
Degradation
sortase A
Enzymes
Pharmaceutical Preparations

Cita questo

Cusimano, M. G., La Franca, M., Barone, G., Faddetta, T., Schillaci, D., Raimondi, M. V., & Gallo, G. (2019). Novel Sortase A Inhibitors to Counteract Gram-Positive Bacterial Biofilms. In MMCS 2019 - FACING NOVEL CHALLENGES IN DRUG DISCOVERY - 2nd Molecules Medicinal Chemistry Symposium (pagg. 209-209)

Novel Sortase A Inhibitors to Counteract Gram-Positive Bacterial Biofilms. / Cusimano, Maria Grazia; La Franca, Mery; Barone, Giampaolo; Faddetta, Teresa; Schillaci, Domenico; Raimondi, Maria Valeria; Gallo, Giuseppe.

MMCS 2019 - FACING NOVEL CHALLENGES IN DRUG DISCOVERY - 2nd Molecules Medicinal Chemistry Symposium. 2019. pag. 209-209.

Risultato della ricerca: Conference contribution

Cusimano, MG, La Franca, M, Barone, G, Faddetta, T, Schillaci, D, Raimondi, MV & Gallo, G 2019, Novel Sortase A Inhibitors to Counteract Gram-Positive Bacterial Biofilms. in MMCS 2019 - FACING NOVEL CHALLENGES IN DRUG DISCOVERY - 2nd Molecules Medicinal Chemistry Symposium. pagg. 209-209.
Cusimano MG, La Franca M, Barone G, Faddetta T, Schillaci D, Raimondi MV e altri. Novel Sortase A Inhibitors to Counteract Gram-Positive Bacterial Biofilms. In MMCS 2019 - FACING NOVEL CHALLENGES IN DRUG DISCOVERY - 2nd Molecules Medicinal Chemistry Symposium. 2019. pag. 209-209
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title = "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. 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]",
author = "Cusimano, {Maria Grazia} and {La Franca}, Mery and Giampaolo Barone and Teresa Faddetta and Domenico Schillaci and Raimondi, {Maria Valeria} and Giuseppe Gallo",
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TY - GEN

T1 - Novel Sortase A Inhibitors to Counteract Gram-Positive Bacterial Biofilms

AU - Cusimano, Maria Grazia

AU - La Franca, Mery

AU - Barone, Giampaolo

AU - Faddetta, Teresa

AU - Schillaci, Domenico

AU - Raimondi, Maria Valeria

AU - Gallo, Giuseppe

PY - 2019

Y1 - 2019

N2 - 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]

AB - 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]

UR - http://hdl.handle.net/10447/356330

M3 - Conference contribution

SP - 209

EP - 209

BT - MMCS 2019 - FACING NOVEL CHALLENGES IN DRUG DISCOVERY - 2nd Molecules Medicinal Chemistry Symposium

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