Local and Universal Action: The Paradoxes of Indole Signalling in Bacteria

Zarkan, Ashraf; Liu, Junyan; Matuszewska, Marta; Gaimster, Hannah; Summers, David

doi:10.1016/j.tim.2020.02.007

Cited by 59 publications

(67 citation statements)

References 92 publications

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“…Persistent signalling occurs at indole concentrations found in stationary phase cultures. In LB cultures, where most indole is synthesised during stationary phase entry, this is in the range 0.3–0.7 mM 10 , 17 , 27 – 29 . To mimic this, LB cultures of the indole non-producing strain BW25113 ∆ tnaA were supplemented with 0.5 mM indole.…”

Section: Resultsmentioning

confidence: 99%

“…For wild-type cells growing in LB, the concentration of cell-associated indole during the pulse is around 60 mM 11 . An artificial indole pulse can be achieved by adding of 4-5 mM indole to the culture supernatant 16,17 (Indole has a greater affinity for cells compared to the aqueous culture medium, which explains the difference in concentration between the cell-associated and the culture medium 16,17 ). We treated exponentially growing cultures (OD 600 = 0.15) of BW25113 ∆tnaA in LB with 5 mM indole for 20 min.…”

Section: Pulse Signalling Generates Indole-dependent Quinolone Persismentioning

confidence: 99%

“…In persistent signalling, indole is present in the culture for an extended period at a relatively low concentration (< 1 mM). In pulse signalling, intra-cellular indole reaches a high concentration (50 mM) for a short period (10–20 min) during stationary phase entry 16 , 17 .…”

Section: Introductionmentioning

confidence: 99%

“…signalling, intra-cellular indole reaches a high concentration (50 mM) for a short period (10-20 min) during stationary phase entry 16,17 .…”

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confidence: 99%

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Inhibition of indole production increases the activity of quinolone antibiotics against E. coli persisters

Zarkan

Matuszewska

Trigg

et al. 2020

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Persisters are a sub-population of genetically sensitive bacteria that survive antibiotic treatment by entering a dormant state. The emergence of persisters from dormancy after antibiotic withdrawal leads to recurrent infection. Indole is an aromatic molecule with diverse signalling roles, including a role in persister formation. Here we demonstrate that indole stimulates the formation of Escherichia coli persisters against quinolone antibiotics which target the GyrA subunit of DNA gyrase. However, indole has no effect on the formation of E. coli persisters against an aminocoumarin, novobiocin, which targets the GyrB subunit of DNA gyrase. Two modes of indole signalling have been described: persistent and pulse. The latter refers to the brief but intense elevation of intracellular indole during stationary phase entry. We show that the stimulation of quinolone persisters is due to indole pulse, rather than persistent, signalling. In silico docking of indole on DNA gyrase predicts that indole docks perfectly to the ATP binding site of the GyrB subunit. We propose that the inhibition of indole production offers a potential route to enhance the activity of quinolones against E. coli persisters. The decreasing effectiveness of antibiotic therapy represents an unprecedented, worldwide threat to human and animal health. The most widely publicised, and best understood, aspect of this problem is antibiotic resistance. This involves genetic change, through mutation or horizontal gene transfer. The target organism is rendered immune to the antibiotic by inactivation of the drug, alteration of its target or export from the cell 1. A less well studied but increasingly important aspect of the anti-bacterial problem is the ability of small sub-populations (< 1%) of genetically sensitive bacteria to survive high concentrations of antibiotic by entering a dormant or partially-dormant state. These cells are known as antibiotic persisters 2-4. When treated with a bactericidal concentration of an antibiotic, persisters display a temporary, non-heritable phenotype where they survive but do not replicate. When the antibiotic therapy is withdrawn, persisters revert to the growing state, giving rise to a population characterised by the same antibiotic sensitivity as the original population. In contrast, resistant cells continue to grow and divide in the presence of the antibiotic and the resistance phenotype is heritable 5-7. The mechanisms by which persister cells enter a dormant state are not well understood. It has been suggested that the activation of chromosome-encoded toxin-antitoxin systems is an important mechanism 8 although this has recently been questioned 9. Links have also been made to the stringent response and carbon source transitions 10. A few reports 11,12 have suggested a role for the signalling molecule indole and this seems plausible because indole has been known for several years to induce reversible E. coli dormancy 13. Indole is an aromatic signalling molecule produced by over 85 species of bacteria encompassing ...

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Section: Resultsmentioning

confidence: 99%

Section: Pulse Signalling Generates Indole-dependent Quinolone Persismentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

“…signalling, intra-cellular indole reaches a high concentration (50 mM) for a short period (10-20 min) during stationary phase entry 16,17 .…”

mentioning

confidence: 99%

See 2 more Smart Citations

Inhibition of indole production increases the activity of quinolone antibiotics against E. coli persisters

Zarkan

Matuszewska

Trigg

et al. 2020

Sci Rep

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“…(Hidalgo-Romano et al, 2014). Although the exact mechanisms responsible for the effects of indoles have not been determined Lee et al, 2015b;Zarkan et al, 2020), the abundance of indole derivatives presents an opportunity to identify indoles active against super bacteria.…”

Section: Discussionmentioning

confidence: 99%

Antibiofilm and Antivirulence Properties of Indoles Against Serratia marcescens

et al. 2020

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Indole and its derivatives have been shown to interfere with the quorum sensing (QS) systems of a wide range of bacterial pathogens. While indole has been previously shown to inhibit QS in Serratia marcescens, the effects of various indole derivatives on QS, biofilm formation, and virulence of S. marcescens remain unexplored. Hence, in the present study, we investigated the effects of 51 indole derivatives on S. marcescens biofilm formation, QS, and virulence factor production. The results obtained revealed that several indole derivatives (3-indoleacetonitrile, 5-fluoroindole, 6-fluoroindole, 7-fluoroindole, 7-methylindole, 7-nitroindole, 5-iodoindole, 5-fluoro-2methylindole, 2-methylindole-3-carboxaldehyde, and 5-methylindole) dose-dependently interfered with quorum sensing (QS) and suppressed prodigiosin production, biofilm formation, swimming motility, and swarming motility. Further assays showed 6fluoroindole and 7-methylindole suppressed fimbria-mediated yeast agglutination, extracellular polymeric substance production, and secretions of virulence factors (e.g., proteases and lipases). QS assays on Chromobacterium violaceum CV026 confirmed that indole derivatives interfered with QS. The current results demonstrate the antibiofilm and antivirulence properties of indole derivatives and their potentials in applications targeting S. marcescens virulence.

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