title: Application of Dual Inhibition Concept within Looped Autoregulatory Systems toward Antivirulence Agents against Pseudomonas aeruginosa Infections.
abstract: Pseudomonas aeruginosa quorum-sensing (QS) is a sophisticated network of genome-wide regulation triggered in response to population density. A major component is the self-inducing pseudomonas quinolone signal (PQS) QS system that regulates the production of several nonvital virulence- and biofilm-related determinants. Hence, QS circuitry is an attractive target for antivirulence agents with lowered resistance development potential and a good model to study the concept of polypharmacology in autoloop-regulated systems per se. Based on the finding that a combination of PqsR antagonist and PqsD inhibitor synergistically lowers pyocyanin, we have developed a dual-inhibitor compound of low molecular weight and high solubility that targets PQS transcriptional regulator (PqsR) and PqsD, a key enzyme in the biosynthesis of PQS-QS signal molecules (HHQ and PQS). In vitro, this compound markedly reduced virulence factor production and biofilm formation accompanied by a diminished content of extracellular DNA (eDNA). Additionally, coadministration with ciprofloxacin increased susceptibility of PA14 to antibiotic treatment under biofilm conditions. Finally, disruption of pathogenicity mechanisms was also assessed in vivo, with significantly increased survival of challenged larvae in a Galleria mellonella infection model. Favorable physicochemical properties and effects on virulence/biofilm establish a promising starting point for further optimization. In particular, the ability to address two targets of the PQS autoinduction cycle at the same time with a single compound holds great promise in achieving enhanced synergistic cellular effects while potentially lowering rates of resistance development.
authors.affiliation: Helmholtz Institute for Pharmaceutical Research Saarland (HIPS) , Department for Drug Design and Optimization, Campus E8.1, 66123 Saarbrücken, Germany.
authors.forename: Andreas
authors.initials: A
authors.lastname: Thomann
authors.affiliation: Helmholtz Institute for Pharmaceutical Research Saarland (HIPS) , Department for Drug Design and Optimization, Campus E8.1, 66123 Saarbrücken, Germany.
authors.forename: Antonio G G
authors.initials: AG
authors.lastname: de Mello Martins
authors.affiliation: Helmholtz Institute for Pharmaceutical Research Saarland (HIPS) , Department for Drug Design and Optimization, Campus E8.1, 66123 Saarbrücken, Germany.
authors.forename: Christian
authors.initials: C
authors.lastname: Brengel
authors.affiliation: Helmholtz Institute for Pharmaceutical Research Saarland (HIPS) , Department for Drug Design and Optimization, Campus E8.1, 66123 Saarbrücken, Germany.
authors.forename: Martin
authors.initials: M
authors.lastname: Empting
authors.affiliation: Helmholtz Institute for Pharmaceutical Research Saarland (HIPS) , Department for Drug Design and Optimization, Campus E8.1, 66123 Saarbrücken, Germany.|Department of Pharmacy, Pharmaceutical and Medicinal Chemistry, Saarland University , Campus C2.3, 66123 Saarbrücken, Germany.
authors.forename: Rolf W
authors.initials: RW
authors.lastname: Hartmann
mesh_terms: D000818:Animals; D000900:Anti-Bacterial Agents / Q000737:chemistry / Q000494:pharmacology*; D001426:Bacterial Proteins / Q000235:genetics / Q000378:metabolism; D018441:Biofilms / Q000187:drug effects* / Q000254:growth & development; D055808:Drug Discovery; D015964:Gene Expression Regulation, Bacterial / Q000187:drug effects; D006801:Humans; D007915:Lepidoptera / Q000382:microbiology; D009842:Oligopeptides / Q000235:genetics / Q000378:metabolism; D011552:Pseudomonas Infections / Q000188:drug therapy* / Q000382:microbiology; D011550:Pseudomonas aeruginosa / Q000187:drug effects* / Q000235:genetics / Q000472:pathogenicity / Q000502:physiology; D011710:Pyocyanine / Q000235:genetics / Q000378:metabolism; D015363:Quinolones / Q000378:metabolism; D053038:Quorum Sensing / Q000187:drug effects*; D037521:Virulence Factors / Q000235:genetics / Q000378:metabolism
chemical_list: C407944:2-heptyl-3-hydroxy-4-quinolone; D000900:Anti-Bacterial Agents; D001426:Bacterial Proteins; D009842:Oligopeptides; D015363:Quinolones; D037521:Virulence Factors; C042453:pyoverdin; D011710:Pyocyanine