Synthesis, antibiofilm activity and molecular docking of N-acylhomoserine lactones containing cinammic moieties.

We prepared a series of cinnamoyl-containing furanones by an affordable and short synthesis. The nineteen compounds hold a variety of substituents including electron-donating, electron-withdrawing, bulky and meta-substituted phenyls, as well as heterocyclic rings. Compounds showed antibiofilm activity in S. aureus, K. pneumoniae and, more pronounced, against P. aeruginosa. The disruption of quorum sensing (QS) was tested using the violacein test and molecular docking predicted the antagonism of LasR as a plausible mechanism of action. The trimethoxylated and diene derivatives showed the best antibiofilm and anti-QS properties, thus becoming candidates for further modifications.

Design of ß-Keto Esters with Antibacterial Activity: Synthesis, In Vitro Evaluation, and Theoretical Assessment of Their Reactivity and Quorum-Sensing Inhibition Capacity.

This work proposes the design of ß-keto esters as antibacterial compounds. The design was based on the structure of the autoinducer of bacterial quorum sensing, N-(3-oxo-hexanoyl)-l-homoserine lactone (3-oxo-C6-HSL). Eight ß-keto ester analogues were synthesised with good yields and were spectroscopically characterised, showing that the compounds were only present in their ß-keto ester tautomer form. We carried out a computational analysis of the reactivity and ADME (absorption, distribution, metabolism, and excretion) properties of the compounds as well as molecular docking and molecular dynamics calculations with the LasR and LuxS quorum-sensing (QS) proteins, which are involved in bacterial resistance to antibiotics. The results show that all the compounds exhibit reliable ADME properties and that only compound 7 can present electrophile toxicity. The theoretical reactivity study shows that compounds 6 and 8 present a differential local reactivity regarding the rest of the series. Compound 8 presents the most promising potential in terms of its ability to interact with the LasR and LuxS QS proteins efficiently according to its molecular docking and molecular dynamics calculations. An initial in vitro antimicrobial screening was performed against the human pathogenic bacteria Pseudomonas aeruginosa and Staphylococcus aureus as well as the phytopathogenic bacteria Pseudomonas syringae and Agrobacterium tumefaciens. Compounds 6 and 8 exhibit the most promising results in the in vitro antimicrobial screening against the panel of bacteria studied.

Pseudomonas aeruginosa LasR overexpression leads to a RsaL-independent pyocyanin production inhibition in a low phosphate condition.

Several Pseudomonas aeruginosa virulence-related traits like pyocyanin are regulated by an intricate regulatory network called quorum sensing (QS) that relies on transcriptional regulators that are activated through binding to a self-produced molecule called an autoinducer (AI). QS is composed of three systems, Las, Rhl and Pqs. In the Las system, the regulatory protein LasR interacts with its AI to activate the other two QS systems. In turn, the Rhl and Pqs systems regulate the expression of multiple virulence-related genes, such as the genes of the reiterated operons phzA1B1C1D1E1F1G1 and phzA2B2C2D2E2F2G2 involved in pyocyanin production. The Las system also regulates the negative regulator RsaL, which provides negative feedback to the QS-response, including repression of pyocyanin synthesis genes. In this work, we describe that LasR can act as a negative regulator of phzA1 transcription and hence of pyocyanin production and that this regulation is independent of RsaL activity. This work contributes to the understanding of QS-dependent pyocyanin production and demonstrates a previously uncharacterized role of LasR as a repressor.

Molecular docking, and anti-biofilm activity of gold-complexed sulfonamides on Pseudomonas aeruginosa.

The antibacterial activity of sulfadiazine Au-PPh3, sulfadiazine Ph2P-Au-Au-PPh2, sulfamethoxazole Au-PPh3, sulfamethoxazole Ph2P-Au-Au-PPh2, sulfamethoxazole Au-PPh3 were tested against Pseudomonas aeruginosa. The antibacterial activity of sulfonamide was tested against P. aeruginosa through the MIC assay, quantitative analysis of biofilm inhibition and observation of biofilm formation with fluorescence microscopy. Besides, the compounds presented remarkable inhibition of P. aeruginosa biofilm formation. Furthermore, molecular docking was performed to identify the key structural features of these compounds with the binding site of the LasR receptor.