Altering the Communication Networks of Multispecies Microbial Systems Using a Diverse Toolbox of AI-2 Analogues

Abstract

There have been intensive efforts to find small molecule antagonists for bacterial quorum sensing (QS) mediated by the "universal" QS autoinducer, AI-2. Previous work has shown that linear and branched acyl analogues of AI-2 can selectively modulate AI-2 signaling in bacteria. Additionally, LsrK-dependent phosphorylated analogues have been implicated as the active inhibitory form against AI-2 signaling. We used these observations to synthesize an expanded and diverse array of AI-2 analogues, which included aromatic as well as cyclic C-1-alkyl analogues. Species-specific analogues that disrupted AI-2 signaling in Escherichia coli and Salmonella typhimurium were identified. Similarly, analogues that disrupted QS behaviors in Pseudomonas aeruginosa were found. Moreover, we observed a strong correlation between LsrK-dependent phosphorylation of these acyl analogues and their ability to suppress QS. Significantly, we demonstrate that these analogues can selectively antagonize QS in single bacterial strains in a physiologically relevant polymicrobial culture.

Exploiting Quorum Sensing To Confuse Bacterial Pathogens

“…First, as anticipated, numerous DPD derivatives were found to be AI-2 QS antagonists in one or multiple bacterial species (209)(210)(211)(212)(213). Second, some of the analogues were found to be synergistic agonists despite having no agonist activity on their own (209)(210)(211)213).…”

“…For example, propyl-DPD and other analogues with longer alkyl chain substitutions were all antagonists of AI-2 QS in E. coli, but only butyl-DPD had antagonistic activity in S. Typhimurium (212). Likewise, cyclic DPD analogues generally inhibited AI-2 QS in E. coli, whereas they either had no activity or functioned as synergistic agonists in S. Typhimurium (209). Additionally, the activity of a given analogue in a given strain may be context dependent, as multiple C1-alkyl DPD derivatives were found to function as either antagonists or synergistic agonists in V. harveyi under different assay conditions (210)(211)(212)(213).…”

“…The best inhibitor identified from these screens was pyrogallol (Table 3), with an IC 50 of 2 M. More recently, there have been multiple reports of the generation and screening of C1-and C2-alkyl DPD derivatives. C1-alkyl derivatives have included linear, branched, cyclic, and aromatic DPD analogues (209)(210)(211)(212)(213), whereas the C2 derivatives tested have thus far been limited to linear substitutions of various alkyl chain lengths (214). None of these C1-or C2-alkyl analogues were more potent inhibitors than the previously identified pyrogallol, but some did have AI-2-modulating activity.…”

“…Biochemical and biological analyses indicate that phosphorylation of AI-2 analogues is necessary but not sufficient for antagonism in E. coli and S. Typhimurium (212) and that both the shape and flexibility of the analogue are likely important for the generation of productive interactions between the analogue and AI-2 receptor (209). Also, given the species specificity exhibited by many of the analogues tested to date, disruption of AI-2 signaling in multispecies environments will likely require multiple AI-2 analogues used in combination that can inhibit AI-2 QS in various species simultaneously (209,212) or in combination with inhibitors of other QS pathways that contribute to virulence alongside the AI-2 pathway. Finally, although AI-2 derivatives do not appear to be cytotoxic toward mammalian cells (211), work will need to be done to assess the stability and efficacy of AI-2 analogues in vivo.…”

Modification of quorum sensing in bacterial cultures

“…Pyrogallol is probably the best inhibitor, but different DPD analogues also have a great future (86)(87)(88).…”