期刊
BIOORGANIC & MEDICINAL CHEMISTRY
卷 27, 期 5, 页码 721-728出版社
PERGAMON-ELSEVIER SCIENCE LTD
DOI: 10.1016/j.bmc.2019.01.010
关键词
Antimicrobial resistance; Pyrrolomycins; Sortase A; Staphylococcus aureus; In-silico docking studies; MAOS; Pharmacokinetics studies; Murein hydrolase activity
资金
- Ministero dell'Istruzione dell'Universita e della Ricerca (MIUR) of the Italian Government [PJ_RIC_FFABR_2017_160599]
New compounds able to counteract staphylococcal biofilm formation are needed. In this study we investigate the mechanism of action of pyrrolomycins, whose potential as antimicrobial agents has been demonstrated. We performed a new efficient and easy method to use microwave organic synthesis suitable for obtaining pyrrolomycins in good yields and in suitable amount for their in vitro in-depth investigation. We evaluate the inhibitory activity towards Sortase A (SrtA), a transpeptidase responsible for covalent anchoring in Gram-positive peptidoglycan of many surface proteins involved in adhesion and in biofilm formation. All compounds show a good inhibitory activity toward SrtA, having IC50 values ranging from 130 to 300 mu M comparable to berberine hydrochloride. Of note compound 1d shows a good affinity in docking experiment to SrtA and exhibits the highest capability to interfere with biofilm formation of S. aureus showing an IC50 of 3.4 nM. This compound is also effective in altering S. aureus murein hydrolase activity that is known to be responsible for degradation, turnover, and maturation of bacterial peptidoglycan and involved in the initial stages of S. aureus biofilm formation.
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