Design, Synthesis and Biological Evaluation of Novel Anthraniloyl-AMP Mimics as PQS Biosynthesis Inhibitors Against Pseudomonas aeruginosa Resistance

Abstract

<jats:p>The Pseudomonas quinolone system (PQS) is one of the three major interconnected quorum sensing signaling systems in Pseudomonas aeruginosa. The virulence factors PQS and HHQ activate the transcription regulator PqsR (MvfR), which controls several activities in bacteria, including biofilm formation and upregulation of PQS biosynthesis. The enzyme anthraniloyl-CoA synthetase (PqsA) catalyzes the first and critical step in the biosynthesis of quinolones; therefore, it is an attractive target for the development of anti-virulence therapeutics against Pseudomonas resistance. Herein, we report the design and synthesis of novel triazole nucleoside-based anthraniloyl- adenosine monophosphate (AMP) mimics. These analogues had a major impact on the morphology of bacterial biofilms and caused significant reduction in bacterial aggregation and population density. However, the compounds showed only limited inhibition of PQS and did not exhibit any effect on pyocyanin production.</jats:p>

Natural Product Rottlerin Derivatives Targeting Quorum Sensing

“…In line with our continuous efforts to develop novel synthetic and natural product analogues as antibacterial agents [ 16 , 17 , 18 ], in this paper, we report the synthesis of biologically interesting analogues of rottlerin and pyranochromene chalcones. The synthesised compounds have been evaluated for quorum sensing, biofilm and pyocyanin inhibition in P. aeruginosa .…”

Inhibitors of Bacterial Extracellular Vesicles

“…PQS is known as a quorum-sensing (QS) molecule in P. aeruginosa which is involved in the production of several bacterial virulence factors and biofilm formation ( Pesci et al, 1999 ; Diggle et al, 2003 ). The production of PQS is initiated with anthranilic acid and involves various enzymatic reactions ( Sabir et al, 2020 ). As a positive regulator of EV production, PQS induces EV production by interacting with the acyl chains and 4-phosphate of bacterial LPS ( Mashburn-Warren et al, 2008 ).…”

Bacterial virulence factors: a target for heterocyclic compounds to combat bacterial resistance

“…In 2020, Sabir et al 116 designed and synthesized fourteen anthranilyl-AMP mimics, which contained triazole linkers as potential inhibitors of Pseudomonas quinolone biosynthesis. However, with the exception of deoxycytidine analogs (27), most of these analogs showed no PQS inhibitory activity against the Pseudomonas aeruginosa reporter chain, which inhibited 30% of the PQS activity at 125 mM.…”