Benzamidobenzoic acids as potent PqsD inhibitors for the treatment of Pseudomonas aeruginosa infections

Abstract

Targeting PqsD is a promising novel approach to disrupt bacterial cell-to-cell-communication in Pseudomonas aeruginosa. In search of selective PqsD inhibitors, two series of benzamidobenzoic acids  one published as RNAP inhibitors and the other as PqsD inhibitors  were investigated for inhibitory activity toward the respective other enzyme. Additionally, novel derivatives were synthesized and biologically evaluated. By this means, the structural features needed for benzamidobenzoic acids to be potent and, most notably, selective PqsD inhibitors were identified. The most interesting compound of this study was the 3-Cl substituted compound 5 which strongly inhibits PqsD (IC 50 6.2 µM) while exhibiting no inhibition of RNAP.

Chemical probes for competitive profiling of the quorum sensing signal synthase PqsD of Pseudomonas aeruginosa

“…Consequently, PqsD has become a highly attractive target and a great amount of work pioneered by the Hartmann group has resulted in inhibitor discovery using a combination of in vitro assay, in silico modelling and chemical lead optimization. Examples of successful inhibitors are represented by the scaffolds of various 2-benzamidobenzoic acids [11,25–26], 2-nitrophenyl derivatives [27–29], ureidothiophene-2-carboxylic acids [24,30], and catechol-based compounds [31]. …”

Exploring the chemical space of ureidothiophene-2-carboxylic acids as inhibitors of the quorum sensing enzyme PqsD from Pseudomonas aeruginosa

“…We further examined the introduction of a cell penetrating peptide (25) at the same position. Again, the inhibitory activity on the cell free level could be retained, but no inhibitory effect in the whole cell assay was observed at the test concentration.…”

Recent Advances in the Discovery of PqsD Inhibitors as Antimicrobial Agents

“…[28] In their work, compound 3 was reported to have PqsD inhibitory activity (IC 50 = 6.2 mm), but no inhibition of RNAP. [29] Introduction of ac hloro group at the 3-position caused an ear tenfoldi mprovement in PqsD inhibitory activity.I nterestingly,asmalli ncrease in RNAP inhibition waso bserved with ah ydroxy group introduced at the 6position, which led to amuch greater improvement in PqsD inhibitory activity.F or instance, compound 4,w ith an IC 50 value of 1.3 mm against PqsD, was~50-foldm ore potent against PqsD than toward RNAP.…”

“…Linezolid ( 29), as ynthetic antibacterial agent,w as approved in 2000 by the US Fooda nd Drug Administration (FDA) for the treatment of community-acquireda nd nosocomialp neumonia, complicated and uncomplicated skin and soft-tissue infections, and infections caused by methicillin-resistant Staphylococcus aureus (MRSA)a nd vancomycin-resistant Enterococci (VRE). [38] This compound has an IC 50 value of~15.9 mm against PqsD (Figure 7).…”