10′(Z),13′(E)-Heptadecadienylhydroquinone Inhibits Swarming and Virulence Factors and Increases Polymyxin B Susceptibility in Proteus mirabilis

Abstract

In this study, we demonstrated that 10′(Z), 13′(E)-heptadecadienylhydroquinone (HQ17-2), isolated from the lacquer tree, could decrease swarming motility and hemolysin activity but increase polymyxin B (PB) susceptibilityof Proteus mirabilis which is intrinsically highly-resistant to PB. The increased PB susceptibility induced by HQ17-2 was also observed in clinical isolates and biofilm-grown cells. HQ17-2 could inhibit swarming in the wild-type and rppA mutant but not in the rcsB mutant, indicating that HQ17-2 inhibits swarming through the RcsB-dependent pathway, a two-component signaling pathway negatively regulating swarming and virulence factor expression. The inhibition of hemolysin activity by HQ17-2 is also mediated through the RcsB-dependent pathway, because HQ17-2 could not inhibit hemolysin activity in the rcsB mutant. Moreover, the finding that HQ17-2 inhibits the expression of flhDC gene in the wild-type and rcsB-complemented strain but not in the rcsB mutant supports the notion. By contrast, HQ17-2 could increase PB susceptibility in the wild-type and rcsB mutant but not in the rppA mutant, indicating that HQ17-2 increases PB susceptibility through the RppA-dependent pathway, a signaling pathway positively regulating PB resistance. In addition, HQ17-2 could inhibit the promoter activities of rppA and pmrI, a gene positively regulated by RppA and involved in PB resistance, in the wild-type but not in the rppA mutant. The inhibition of rppA and pmrI expression caused lipopolysaccharide purified from HQ17-2-treated cells to have higher affinity for PB. Altogether, this study uncovers new biological effects of HQ17-2 and provides evidence for the potential of HQ17-2 in clinical applications.

Serratia marcescens arn , a PhoP-Regulated Locus Necessary for Polymyxin B Resistance

“…It is tempting to suggest that the pathway is a potential target for drug development. In this regard, HQ17-2, a natural product from the lacquer tree, has been shown to inhibit the expression of rppA and pmrI in P. mirabilis (42).…”

Inhibitors of Bacterial Swarming Behavior

“…A 10'(Z),13'(E)-heptadecadienylhydroquinone (HQ17-2) isolated from the lacquert ree inhibited swarming motility of P. mirabilis between 36 and 145 mm through the two-components ystem RcsB which controlst he flhDC genes encoding the flagellar master regulator FlhD 2 C 2 . [110] With exception of tannins, plant metabolites exhibitedc omparably low activity on swarming bacteria.T he mechanisms hereby may be as diversea st he compound classes and range from inhibition of surfactant production to regulatory effects on flagellar gene expression.…”

Proteus mirabilisand Urinary Tract Infections

“…Specifically, P. mirabilis shares common features with swarming by E. coli (68) and Salmonella (69, 70); however, P. mirabilis swarming is famously robust compared to these species and will occur on most laboratory media unless inhibitors are used. Swarming does not typically occur on chemically-defined minimal media (71), and may also be controlled in the laboratory by reducing the concentration of salt to ≤0.5 g/L or by adding inhibitors (e.g., glycerol, pnitrophenyl glycerin, or 4% agar) (72)(73)(74)(75)(76), although the success of these techniques may depend on incubation time, temperature, humidity, and strain of P. mirabilis. Mathematical models have been used to represent P. mirabilis swarming (77-80); these models recapitulate the terracing that occurs during swarm-consolidation cycles and are beginning to address issues such as water channeling.…”