“…7 ), compared with the control. These results indicate that these compounds can attenuate the production of this virulence factor through inhibition of PqsR similar to that shown for other PqsR inhibitors [ 34 , 45 , 46 ]. Fig.…”
Rising numbers of cases of multidrug- and extensively drug-resistant
Pseudomonas aeruginosa
over recent years have created an urgent need for novel therapeutic approaches to cure potentially fatal infections. One such approach is virulence attenuation where anti-virulence compounds, designed to reduce pathogenicity without affording bactericidal effects, are employed to treat infections.
P. aeruginosa
uses the
pqs
quorum sensing (QS) system, to coordinate the expression of a large number of virulence determinants as well as bacterial-host interactions and hence represents an excellent anti-virulence target.
We report the synthesis and identification of a new series of thiazole-containing quinazolinones capable of inhibiting PqsR, the transcriptional regulator of the
pqs
QS system. The compounds demonstrated high potency (IC
50
< 300 nM) in a whole-cell assay, using a mCTX:P
pqsA
-lux
-based bioreporter for the
P. aeruginosa
PAO1-L and PA14 strains. Structural evaluation defined the binding modes of four analogues in the ligand-binding domain of PqsR through X-ray crystallography. Further work showed the ability of 6-chloro-3((2-pentylthiazol-4-yl)methyl)quinazolin-4(3
H
)-one (
18
) and 6-chloro-3((2-hexylthiazol-4-yl)methyl)quinazolin-4(3
H
)-one (
19
) to attenuate production of the PqsR-regulated virulence factor pyocyanin. Compounds
18
and
19
showed a low cytotoxic profile in the A549 human epithelial lung cell line making them suitable candidates for further pre-clinical evaluation.
“…7 ), compared with the control. These results indicate that these compounds can attenuate the production of this virulence factor through inhibition of PqsR similar to that shown for other PqsR inhibitors [ 34 , 45 , 46 ]. Fig.…”
Rising numbers of cases of multidrug- and extensively drug-resistant
Pseudomonas aeruginosa
over recent years have created an urgent need for novel therapeutic approaches to cure potentially fatal infections. One such approach is virulence attenuation where anti-virulence compounds, designed to reduce pathogenicity without affording bactericidal effects, are employed to treat infections.
P. aeruginosa
uses the
pqs
quorum sensing (QS) system, to coordinate the expression of a large number of virulence determinants as well as bacterial-host interactions and hence represents an excellent anti-virulence target.
We report the synthesis and identification of a new series of thiazole-containing quinazolinones capable of inhibiting PqsR, the transcriptional regulator of the
pqs
QS system. The compounds demonstrated high potency (IC
50
< 300 nM) in a whole-cell assay, using a mCTX:P
pqsA
-lux
-based bioreporter for the
P. aeruginosa
PAO1-L and PA14 strains. Structural evaluation defined the binding modes of four analogues in the ligand-binding domain of PqsR through X-ray crystallography. Further work showed the ability of 6-chloro-3((2-pentylthiazol-4-yl)methyl)quinazolin-4(3
H
)-one (
18
) and 6-chloro-3((2-hexylthiazol-4-yl)methyl)quinazolin-4(3
H
)-one (
19
) to attenuate production of the PqsR-regulated virulence factor pyocyanin. Compounds
18
and
19
showed a low cytotoxic profile in the A549 human epithelial lung cell line making them suitable candidates for further pre-clinical evaluation.
“…Biofilms also possibly form nidus at the surface for the attachment of other pathogens that lead to biofilms of multiple bacteria or multiorganisms (Yang et al, 2011). The communication in mixed-organism biofilms is referred to as "quorum sensing" (Hossain et al, 2020) and might induce different biofilm properties than single-organism biofilms (Yang et al, 2011). Although catheter-related colonization of Gram-positive bacteria from skin microbiota (Streptococcus spp.…”
Bacteria and Candidaalbicans are prominent gut microbiota, and the translocation of these organisms into blood circulation might induce mixed-organism biofilms, which warrants the exploration of mixed- versus single-organism biofilms in vitro and in vivo. In single-organism biofilms, Acinetobacter baumannii and Pseudomonas aeruginosa (PA) produced the least and the most prominent biofilms, respectively. C. albicans with P. aeruginosa (PA+CA) induced the highest biofilms among mixed-organism groups as determined by crystal violet straining. The sessile form of PA+CA induced higher macrophage responses than sessile PA, which supports enhanced immune activation toward mixed-organism biofilms. In addition, Candida incubated in pre-formed Pseudomonas biofilms (PA>CA) produced even higher biofilms than PA+CA (simultaneous incubation of both organisms) as determined by fluorescent staining on biofilm matrix (AF647 color). Despite the initially lower bacteria during preparation, bacterial burdens by culture in mixed-organism biofilms (PA+CA and PA>CA) were not different from biofilms of PA alone, supporting Candida-enhanced Pseudomonas growth. Moreover, proteomic analysis in PA>CA biofilms demonstrated high AlgU and mucA with low mucB when compared with PA alone or PA+CA, implying an alginate-related mucoid phenotype in PA>CA biofilms. Furthermore, mice with PA>CA biofilms demonstrated higher bacteremia with more severe sepsis compared with mice with PA+CA biofilms. This is possibly due to the different structures. Interestingly, l-cysteine, a biofilm matrix inhibitor, attenuated mixed-organism biofilms both in vitro and in mice. In conclusion, Candida enhanced Pseudomonas alginate–related biofilm production, and Candida presentation in pre-formed Pseudomonas biofilms might alter biofilm structures that affect clinical manifestations but was attenuated by l-cysteine.
“…These 29 MVfR antagonists were first described by the Hartmann group in 2012 and 2013 using a ligand-based drug design approach [ 29 ] and fragment identification approach using surface plasmon resonance screening, respectively [ 24 ]. After going through the literature, an additional list of 11 manually curated active ligands was created [ 30 , 59 , 60 , 61 ]. Only the ligands that presented activity toward PqsR/MvfR were selected (i.e., compounds with IC50 values), raising the total of active molecules in the test set to 40.…”
Pseudomonas aeruginosa is an opportunistic Gram-negative bacterium responsible for acute and chronic infections in planktonic state or in biofilms. The sessile structures are known to confer physical stability, increase virulence, and work as a protective armor against antimicrobial compounds. P. aeruginosa can control the expression of genes, population density, and biofilm formation through a process called quorum sensing (QS), a rather complex and hierarchical system of communication. A recent strategy to try and overcome bacterial resistance is to target QS proteins. In this study, a combined multi-level computational approach was applied to find possible inhibitors against P. aeruginosa QS regulator protein MvfR, also known as PqsR, using a database of approved FDA drugs, as a repurposing strategy. Fifteen compounds were identified as highly promising putative MvfR inhibitors. On those 15 MvfR ligand complexes, molecular dynamic simulations and MM/GBSA free-energy calculations were performed to confirm the docking predictions and elucidate on the mode of interaction. Ultimately, the five compounds that presented better binding free energies of association than the reference molecules (a known antagonist, M64 and a natural inducer, 2-nonyl-4-hydroxyquinoline) were highlighted as very promising MvfR inhibitors.
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