Abstract
Sortase A inhibition is a well establish strategy for decreasing bacterial virulence by affecting numerous key processes that control biofilm formation, host cell entry, evasion and suppression of the immune response and acquisition of essential nutrients. A meta-analysis of structures known to act as Sortase A inhibitors provided the starting point for identifying a new potential scaffold. Based on this template a series of new potential Sortase A inhibitors, that contain the 2-phenylthiazole moiety, were synthesized. The physicochemical characterisation confirmed the identity of the proposed structures. Antibacterial activity evaluation showed that the new compounds have a reduced activity against bacterial cell viability. However, the compounds prevent biofilm formation at very low concentrations, especially in the case of E. faecalis. Molecular docking studies performed estimate that this is most likely due to the inhibition of Sortase A. The new compounds could be used as add-on therapies together with known antibacterial agents in order to combat multidrug-resistance enterococcal infections.
Highlights
Preventing antibiotic resistance and identifying new antibiotics that are active against the multidrug resistant bacteria are major current concerns [1,2]
Considering the top binding conformations of C1–8 to the active site of the Sortase A of E. faecalis (EfSRT_29212) we further focused on specific AA binding interactions
We synthesized and characterized eight compounds containing a phenylthiazole within a pentacyclic system
Summary
Preventing antibiotic resistance and identifying new antibiotics that are active against the multidrug resistant bacteria are major current concerns [1,2]. Gram-positive bacteria are common causes of nosocomial bloodstream and other infections. Methicillin-resistant Staphylococcus aureus (MRSA) and vancomycin-resistant enterococci (VRE) are the most imperative concern [3]. Gram-positive bacteria have a thick cell wall that surrounds the plasma membrane. This cell wall is composed of peptidoglycan that serves as a matrix for the covalent attachment of wall teichoic acid, surface proteins and polysaccharide capsule [4,5]. Sortases are cysteine transpeptidases that are able to Molecules 2017, 22, 1827; doi:10.3390/molecules22111827 www.mdpi.com/journal/molecules
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