According to the CDCs 2019 Antibiotic Resistance Threats Report, infections caused by multidrug-resistant P. aeruginosa compromised about 32,600 hospitalized patients and 2,700 deaths in the United States during 2017 [1]. Therefore, new agents against Pseudomonas aeruginosa are an urgent necessity [2]. Transcription factors (TF) associated with quorum sensing (QS) are promising targets for the development of new adjuvants against infection by this pathogen [3]. In order to find key structural features for the agonist and antagonist activity, we built and analyzed chemoinformatically the molecular dataset (DS) of the TF PqsR related to the QS in P. aeruginosa. PqsR DS was built from research articles, review papers, PubChem Bioassay [4] and ChEMBL [5] databases. Then, computational simulations were done to associate the key PqsR amino acids with the type of activity. To do so, DS was subjected to a maximum common substructure (MCS) analysis, molecular docking, protein (PqsR)-ligand interaction fingerprint (PLIF) and molecular dynamics simulations with the MCS results. PqsR DS contains 63 molecules, 12 agonists, 17 antagonists, and the remaining inactive. MCS analysis showed that DS molecules, with small structural changes display agonist and antagonist activities, even inactive. PLIF’s and molecular dynamics simulations gave us the possibility to associate key residues with agonist and antagonist activities: for the agonist activity, Ser 196 and Leu 197 were associated in both analyses, while Gln 194 and Arg 209 could be important according only to molecular dynamics. Lastly, Ala 102, Phe 221, Leu 207, and Ile 149 shown to be important for the antagonist activity; Ala 102 was confirmed by the two methods, Phe 221 by PLIF analysis, and the rest of them only by molecular dynamics simulations. The knowledge of the PqsR behavior in the face of the agonist and antagonist activity will allow us to design new antagonist molecules and optimize them. These results give us a different panorama in the research of antibiotics against P. aeruginosa.

Key molecular features and amino acid residues for the agonist and antagonist activity of the transcriptional factor PqsR from P. aeruginosa

ACS Spring Meeting 2021

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