Toxin YafQ increases persister cell formation by reducing indole signalling

Abstract

Persister cells survive antibiotic and other environmental stresses by slowing metabolism. Since toxins of toxin/antitoxin (TA) systems have been postulated to be responsible for persister cell formation, we investigated the influence of toxin YafQ of the YafQ/DinJ Escherichia coli TA system on persister cell formation. Under stress, YafQ alters metabolism by cleaving transcripts with in-frame 5'-AAA-G/A-3' sites. Production of YafQ increased persister cell formation with multiple antibiotics, and by investigating changes in protein expression, we found that YafQ reduced tryptophanase levels (TnaA mRNA has 16 putative YafQ cleavage sites). Consistently, TnaA mRNA levels were also reduced by YafQ. Tryptophanase is activated in the stationary phase by the stationary-phase sigma factor RpoS, which was also reduced dramatically upon production of YafQ. Tryptophanase converts tryptophan into indole, and as expected, indole levels were reduced by the production of YafQ. Corroborating the effect of YafQ on persistence, addition of indole reduced persistence. Furthermore, persistence increased upon deleting tnaA, and persistence decreased upon adding tryptophan to the medium to increase indole levels. Also, YafQ production had a much smaller effect on persistence in a strain unable to produce indole. Therefore, YafQ increases persistence by reducing indole, and TA systems are related to cell signalling.

Roles of Indole as an Interspecies and Interkingdom Signaling Molecule

“…Indole also increases the formation of antibiotic-tolerant persister cells, and the process involved is possibly linked to oxidative stress and phage shock pathways [12], which supports previous results that indole increases antibiotic resistance via multidrug transport [11,33,34]. In contrast, it has also been reported that indole decreases persister formation via phosphodiesterase DosP, which reduces cyclic adenosine monophosphate concentrations that are required to activate TnaA [35], and via the toxin protein YafQ, which cleaves TnaA mRNA [36]. The discrepancy in the role of indole and persistence is probably attributable to the different persister assay conditions used in the studies.…”

Comprehensive Proteomic and Metabolomic Signatures of Nontypeable Haemophilus influenzae-Induced Acute Otitis Media Reveal Bacterial Aerobic Respiration in an Immunosuppressed Environment

“…Indole can inhibit N-acylated homoserine lactone-mediated quorum signaling associated with virulence and biofilm formation in Vibrio species (140). Decreases in indole concentration through changes in bacterial metabolic activity or release of factors that interfere with tryptophanase production, coincides with increased bacterial persistence and increased biofilm formation (142,143).…”

Halogenated indoles eradicate bacterial persister cells and biofilms

“…In particular, indole has been reported to modulate biofilm formation in various bacteria (Lee et al 2007; Oh et al 2012; Lee et al 2015) and persister formation in E. coli (Vega et al 2012, 2013; Hu et al 2015; Kwan et al 2015). Of note, functional groups on the indole moiety control biofilm formation (Lee et al 2009), the production of virulence factors and antibiotic resistance in Pseudomonas aeruginosa (Lee et al 2009, 2012), spore maturation in Paenibacillus alvei (Kim et al 2011), and the production of immune-evasive staphyloxanthin in S. aureus (Lee et al 2013).…”