Discovery of an inhibitor of the production of the Pseudomonas aeruginosa virulence factor pyocyanin in wild-type cells

Abstract

SummaryPyocyanin is a small molecule produced by Pseudomonas aeruginosa that plays a crucial role in the pathogenesis of infections by this notorious opportunistic pathogen. The inhibition of pyocyanin production has been identified as an attractive antivirulence strategy for the treatment of P. aeruginosa infections. Herein, we report the discovery of an inhibitor of pyocyanin production in cultures of wild-type P. aeruginosa which is based around a 4-alkylquinolin-2(1H)-one scaffold. To the best of our knowledge, this is the first reported example of pyocyanin inhibition by a compound based around this molecular framework. The compound may therefore be representative of a new structural sub-class of pyocyanin inhibitors, which could potentially be exploited in in a therapeutic context for the development of critically needed new antipseudomonal agents. In this context, the use of wild-type cells in this study is notable, since the data obtained are of direct relevance to native situations. The compound could also be of value in better elucidating the role of pyocyanin in P. aeruginosa infections. Evidence suggests that the active compound reduces the level of pyocyanin production by inhibiting the cell–cell signalling mechanism known as quorum sensing. This could have interesting implications; quorum sensing regulates a range of additional elements associated with the pathogenicity of P. aeruginosa and there is a wide range of other potential applications where the inhibition of quorum sensing is desirable.

Biosynthesis of Cittilins, Unusual Ribosomally Synthesized and Post-translationally Modified Peptides from Myxococcus xanthus

“…Given these results, we conclude that cittilin A has poor cell entry capability for E. coli, which impedes the inhibition of intracellular CsrA and may explain why cittilin A showed no inhibition of pyocyanin production when administered to Pseudomonas aeruginosa, an assay commonly used to evaluate antivirulence efficiency of small- molecules (Supporting Information). 49 To support the assumption of poor pharmacokinetics, studies using cittilin A with improved cell entry properties through coupling with iron chelators might give further insights into its biological function. At present we cannot exclude that the biological function of cittilins is distinct from its potential activity as an anti-infective pathoblocker.…”

Cellular Effects of Pyocyanin, a Secreted Virulence Factor of Pseudomonas aeruginosa

“…To date, there have been a small number of studies assessing the effects of pharmacological agents on the production of PCN from P. aeruginosa in vitro. However, these have not been assessed in vivo [ 92 , 93 , 94 , 95 , 96 , 97 , 98 ]. Furthermore, numerous compounds with antioxidant properties have been assessed for their protective properties in vitro, however these have not been evaluated for their effectiveness in in vivo studies [ 48 ].…”

Structure-based Druggability Assessment of Anti-virulence Targets from Pseudomonas aeruginosa

“…As mentioned before, several anti-virulence drug-design efforts rely on pyocyanin inhibition as a readout 64,65,66,67 , surprisingly very few efforts have been made to target enzymes that are responsible for the biosynthesis of this virulence factor. Therefore, the assessment of the pyocyanin biosynthetic enzymes as druggable targets remains to be determined.…”