A Novel Scaffold to Fight Pseudomonas Aeruginosa Pyocyanin Production: Early Steps to Novel Antivirulence Drugs

Abstract

Aim: Although bacterial resistance is a growing concern worldwide, the development of antibacterial drugs has been steadily decreasing. One alternative to fight this issue relies on reducing the bacteria virulence without killing it. PhzS plays a pivotal role in pyocyanin production in Pseudomonas aeruginosa. Results: A total of 31 thiazolidinedione derivatives were evaluated as putative PhzS inhibitors, using thermo shift assays. Compounds that significantly shifted PhzS's Tm had their mode of inhibition (cofactor competitor) and affinity calculated by thermo shift assays as well. The most promising compound (E)-5-(4-((4-oxo-3-phenyl-3,4-dihydroquinazolin-2-yl)methoxy)benzylidene)thiazolidine-2,4-dione had their affinity confirmed by microscale thermophoresis (K_d = 18 μM). Cellular assays suggest this compound reduces pyocyanin production in vitro, but does not affect P. aeruginosa viability. Conclusion: The first inhibitor of PhzS is described.

Keywords: :

• cell-based assay
• mechanism of inhibition
• Pseudomonas aeruginosa
• thermal shift assays
• thiazolidinedione

Supplementary data

To view the supplementary data that accompany this paper please visit the journal website at:www.tandfonline.com/doi/full/10.2217/epi-2016-0184

Acknowledgments

The authors would like to acknowledge J Parsons (Maryland University) for providing the plasmids with PhzS from Pseudomonas aeruginosa and PS Lacerda for its technical support to run DSF-fitting and APA Pinto for technical support in microscale thermophoresis assays.

Financial & competing interests disclosure

This study was supported by FAPESP (2016/13884-2), Equipamento Multi-Usuário (EMU/FAPESP)/CIBFar/Grupo de Cristalografia/IFSC), CNPq (310138/2017-5 and 421304/2018-9), CAPES (TQF’ fellowship 88881.134191/2016-01) and Zagazig University. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

No writing assistance was utilized in the production of this manuscript.