Interkingdom signal indole inhibits Pseudomonas aeruginosa persister cell waking

Abstract

Aims Persister cells are stressed cells that have transient tolerance to antibiotics; these cells undergo no genetic change, but instead, their tolerance is due to reduced metabolism. Unfortunately, little is known about how persisters resuscitate, so we explored the waking of cells in the presence of the interkingdom signal indole. Methods and Results To generate a large population of persister cells, we induced the persister phenotype in the opportunistic pathogen Pseudomonas aeruginosa by pretreating cells with carbonyl cyanide m‐chlorophenylhydrazone to reduce translation by depleting ATP levels, and found, via single cell observations, that proline is sufficient to wake the persister cells. P. aeruginosa is often present in the gastrointestinal tract, and indole from commensal bacteria such as Escherichia coli has been shown to inhibit P. aeruginosa quorum sensing and pathogenicity without influencing growth. Furthermore, indole is not toxic to P. aeruginosa persister cells. However, we find here that physiological concentrations of indole inhibit P. aeruginosa persister cell resuscitation with an efficiency of higher than 95%. Critically, when contacted with E. coli stationary‐phase cultures, the indole produced by E. coli completely inhibits persister cell resuscitation of P. aeruginosa. Conclusions Therefore, E. coli has devised a method to outcompete its competitors by preventing their resuscitation with indole. Significance and Impact of the Study This work provides insight into why indole is produced by commensal bacteria.

Combatting Persister Cells With Substituted Indoles

“…In addition to killing persister cells, indole also has another remarkable trait: it selectively allows E. coli cells to resuscitate from dormancy while preventing other cells from resuscitating (Zhang W. et al, 2019). Specifically, indole has no effect on E. coli resuscitation, but indole prevents P. aeruginosa persisters from waking (Zhang W. et al, 2019). Furthermore, indole allows E. coli to outcompete P. aeruginosa (Zhang W. et al, 2019).…”

Strategies to Combat Persistent Infectious Diseases

“…These dormant bacteria can indeed rapidly restore their wild-type phenotype (and become susceptible again) when drug pressure is removed, reactivating their metabolism. The signaling pathways involved in this "awaking" process are being further investigated [17,18]. Persister cells can survive in immune-compromised patients but also in patients where antibiotics do not effectively kill pathogenic bacteria by immune-evasion strategies [17].…”

In vitro activity of AST-120 that suppresses indole signaling in Escherichia coli, which attenuates drug tolerance and virulence

“…AST-120 administration may therefore contribute to therapies for these enteric infections. On the other hand, indole suppresses virulence of P. aeruginosa and Staphylococcus aureus, increases drug susceptibility in Lysobacter species and inhibits P. aeruginosa persister cell resuscitation [11][12][39][40]. Therefore, we have to note that AST-120 may exhibit detrimental aspects in some of cases.…”

“…Indole controls diverse cellular functions of bacteria including drug resistance, drug tolerance, biofilm formation and virulence as a signal molecule [10][11][12]. Previously, we found that indole increases expression of genes that encode proteins for drug efflux pumps and the type III secretion system, which contribute to drug tolerance and pathogenicity in host epithelial cells, respectively, in species, such as the food-borne pathogen enterohaemorrhagic E. coli (EHEC) [13][14].…”