Quorum sensing (QS) is a process of cell–cell communication for bacteria such as E. coli and Salmonella that cause foodborne diseases, with the production, release, and detection of autoinducer (AI) molecules that participate in the regulation of virulence genes. All of these proteins are useful in coordinating collective behavior, the expression of virulence factors, and the pathogenicity of Gram-negative bacteria. In this work, we review the natural or synthetic inhibitor molecules of QS that inactivate the autoinducer and block QS regulatory proteins in E. coli and Salmonella. Furthermore, we describe mechanisms of QS inhibitors (QSIs) that act as competitive inhibitors, being a useful tool for preventing virulence gene expression through the downregulation of AI-2 production pathways and the disruption of signal uptake. In addition, we showed that QSIs have negative regulatory activity of genes related to bacterial biofilm formation on clinical artifacts, which confirms the therapeutic potential of QSIs in the control of infectious pathogens. Finally, we discuss resistance to QSIs, the design of next-generation QSIs, and how these molecules can be leveraged to provide a new antivirulence therapy to combat diseases caused by E. coli or Salmonella.

Search inhibitors of Quorum Sensing (QS) in Pseudomonas aeruginosa are challenging to find therapies due to the broad antibiotic resistance. Therefore, this study aimed to probe ten aromatic compounds as inhibitors of three transcriptional regulators of QS in P. aeruginosa. The methodology consisted in determining the Binding Gibbs Energy (BGE) with software Chimera (tool vina) and Mcule, comparing the averages by the Tukey method (p≤0.05) to find inhibitors of QS. Subsequently, the LD₅₀ in the mice model was evaluated by three QSAR models, and the in silico pharmacokinetic values were obtained from the ADME (the absorption distribution metabolism excretion) and PubChem databases. Found three potential inhibitors of RhlR with the lower BGE values in the range -6.70±0.21 to -7.43±0.35 kcal/mol. On the other side, all compounds were acceptable for Lipinski's rule of fives and the in silico oral mice LD₅₀ and ADME values. Concluding, the ferulic acid and eugenol showed the best total BGE values (-75.07±0.892 and -70.36±1.022 kcal/mol), proposing them as a new therapy against the virulence of P. aeruginosa. Finally, the in silico studies have demonstrated are reproducible and valuable for putative QS inhibitors predicting and obtaining new studies derivatives from the results obtained in the present study.

Aim The present investigation was aimed at isolating and identifying bacterial strains from cured vanilla beans. Additionally, the study focused on evaluating bacterial processes pertaining to the aromatic compounds production (ACP). Methods and Results Three bacteria were isolated from Vanilla planifolia beans, previously subjected to the curing process. According to morphological, biochemical and 16S rRNA analysis, the strains were identified as Citrobacter sp, Enterobacter sp, and Pseudomonas sp. The polygalacturonase activity (PGA) was determined using the drop, cup plate and DNS methods. Aromatic compounds production (ACP) was analyzed by cup plate method using FA as substrate and quantified by HPLC (ppm), the functional groups of vanillic acid (VA) were identified by FT‐IR and the aromatic compounds (AC) resistance was determined and reported as MIC. Citrobacter sp, Enterobacter sp, and Pseudomonas showed PGA (70.31 ± 364, 76.07 ± 12.47 and 51 ± 10.92 U mL^‐1 respectively), were producers of VA (3.23 ± 0.49 ppm, 324 ± 41 ppm and 265.99 ± 11.61 ppm, respectively) and were resistant to AC. Conclusions The Gram‐negative bacteria isolated from Vanilla planifolia beans were responsible for ACP. Significance and Impact of the Study This is the first evidence for the role of Gram‐negative bacterial isolates from cured Mexican Vanilla planifolia beans in the process related to ACP.

RESUMEN La búsqueda de inhibidores de Quorum sensing (QS) en bacterias Gram-negativas es de importancia por su patogenicidad, por ello actualmente se buscan nuevas alternativas para inhibir la virulencia. El objetivo del presente estudio fue determinar la energía libre de Gibbs (-ΔG) por medio del acoplamiento molecular de 11 compuestos aromáticos con el regulador CviR de QS en Chromobacterium violaceum, obtener los parámetros farmacocinéticos y preclínicos de los mejores inhibidores de QS. Evaluando la -ΔG por 2 programas (Chimera 1.14 y mcule) comparando los promedios por método Tukey (p≤0.05) y representando la unión ligando-proteína por medio de modelos de lazos y listones. Además de analizar las interacciones entre los aminoácidos del regulador CviR (puente de hidrogeno y enlaces no covalentes) y los grupos funcionales de los compuestos aromáticos. Finalmente, se realizó un estudio in silico preclínico reportando la Dosis Letal en ratón (DL₅₀) por 3 modelos QSAR y 5 parámetros farmacocinéticos. Los resultados demostraron que al analizar la -ΔG por ambos programas se obtuvieron 5 fuertes inhibidores de QS; el ácido ferúlico (-6.37±0.21), el ácido hidroxicinámico (-6.53±0.35), 4-hidroxibenzaldehído (6.6±0.61), el eugenol (-6.2±0.38) y el isoeugenol (-6.23±0.59). Obteniendo que cada compuesto inhibe la actividad de CviR por un mecanismo de bloqueo del dominio de unión al autoinductor-1. Además, se obtuvieron valores significativos de DL₅₀ sin reportar toxicidad en ratón y valores farmacocinéticos aceptables de los 5 inhibidores seleccionados. Concluyendo que los inhibidores podrían ser objetivo de investigación como terapia alternativa contra la patogénesis de C. violaceum. ABSTRACT The search for inhibitors of Quorum sensing (QS) in Gram-negative bacteria is important due to its pathogenicity, therefore new alternatives are being sought to inhibit its virulence. The objective of the present study was to determine the Gibbs free energy (-ΔG) through a molecular coupling of 11 aromatic compounds with the CviR regulator of QS in Chromobacterium violaceum and to obtain the pharmacokinetic and preclinical parameters of the best QS inhibitors. Evaluating the -ΔG by 2 programs (Chimera 1.14 and mcule) comparing the averages by Tukey method (p≤0.05) and representing the ligand-protein binding employing loops and ribbons models. Furthermore, the interactions between the amino acids of the QS regulator (hydrogen bridge and non-covalent bonds) and the functional groups of aromatic compounds were analyzed. Finally, a preclinical in silico study was carried out reporting the Lethal Dose in mice (LD₅₀) by 3 QSAR models and 5 pharmacokinetic parameters. The results showed that when analyzing the -ΔG by both programs, 5 strong QS inhibitors were obtained: ferulic acid (-6.37 ± 0.21), hydroxycinnamic acid (-6.53 ± 0.35), 4-hydroxybenzaldehyde (6.6 ± 0.61), eugenol (-6.2 ± 0.38), and isoeugenol (-6.23 ± 0.59). Obtaining that each compound inhibits the activity of CviR by a blocking mechanism of the autoinducer-1 binding domain of CviR. Also, significant LD₅₀ values were obtained without reporting mouse toxicity and acceptable pharmacokinetic values of the 5 selected inhibitors. Concluding that the inhibitors could be the target of research as an alternative therapy against the pathogenesis of C. violaceum.