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Bioorg Med Chem. 2019 Mar 1;27(5):721-728. doi: 10.1016/j.bmc.2019.01.010. Epub 2019 Jan 16.

Pyrrolomycins as antimicrobial agents. Microwave-assisted organic synthesis and insights into their antimicrobial mechanism of action.

Author information

1
Department of Biological, Chemical and Pharmaceutical Sciences and Technologies, (STEBICEF), University of Palermo, via Archirafi 32, 90123 Palermo, Italy. Electronic address: mariavaleria.raimondi@unipa.it.
2
Drug Sciences Department, Medicinal Chemistry and Pharmaceutical Technology Section, University of Pavia, via Taramelli 12, 27100 Pavia, Italy. Electronic address: roberta.listro01@universitadipavia.it.
3
Department of Biological, Chemical and Pharmaceutical Sciences and Technologies, (STEBICEF), University of Palermo, via Archirafi 32, 90123 Palermo, Italy. Electronic address: mariagrazia.cusimano@unipa.it.
4
Department of Biological, Chemical and Pharmaceutical Sciences and Technologies, (STEBICEF), University of Palermo, via Archirafi 32, 90123 Palermo, Italy. Electronic address: mery.lafranca@unipa.it.
5
Department of Biological, Chemical and Pharmaceutical Sciences and Technologies, (STEBICEF), University of Palermo, via Archirafi 32, 90123 Palermo, Italy. Electronic address: teresa.faddetta@unipa.it.
6
Department of Biological, Chemical and Pharmaceutical Sciences and Technologies, (STEBICEF), University of Palermo, via Archirafi 32, 90123 Palermo, Italy. Electronic address: giuseppe.gallo@unipa.it.
7
Department of Biological, Chemical and Pharmaceutical Sciences and Technologies, (STEBICEF), University of Palermo, via Archirafi 32, 90123 Palermo, Italy. Electronic address: domenico.schillaci@unipa.it.
8
Drug Sciences Department, Medicinal Chemistry and Pharmaceutical Technology Section, University of Pavia, via Taramelli 12, 27100 Pavia, Italy. Electronic address: simona.collina@unipv.it.
9
APP Latvian Biomedical Research and Study Centre (BMC), Rātsupītes iela 1, LV-1067 Rīga, Latvia. Electronic address: ainleo@biomed.lu.lv.
10
Department of Biological, Chemical and Pharmaceutical Sciences and Technologies, (STEBICEF), University of Palermo, via Archirafi 32, 90123 Palermo, Italy. Electronic address: giampaolo.barone@unipa.it.

Abstract

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 µM 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.

KEYWORDS:

Antimicrobial resistance; In-silico docking studies; MAOS; Murein hydrolase activity; Pharmacokinetics studies; Pyrrolomycins; Sortase A; Staphylococcus aureus

PMID:
30711310
DOI:
10.1016/j.bmc.2019.01.010

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