Salmonella typhimurium intercepts Escherichia coli signaling to enhance antibiotic tolerance

Abstract

Bacterial communication plays an important role in many populationbased phenotypes and interspecies interactions, including those in host environments. These interspecies interactions may prove critical to some infectious diseases, and it follows that communication between pathogenic bacteria and commensal bacteria is a subject of growing interest. Recent studies have shown that Escherichia coli uses the signaling molecule indole to increase antibiotic tolerance throughout its population. Here, we show that the intestinal pathogen Salmonella typhimurium increases its antibiotic tolerance in response to indole, even though S. typhimurium does not natively produce indole. Increased antibiotic tolerance can be induced in S. typhimurium by both exogenous indole added to clonal S. typhimurium populations and indole produced by E. coli in mixedmicrobial communities. Our data show that indole-induced tolerance in S. typhimurium is mediated primarily by the oxidative stress response and, to a lesser extent, by the phage shock response, which were previously shown to mediate indole-induced tolerance in E. coli. Further, we find that indole signaling by E. coli induces S. typhimurium antibiotic tolerance in a Caenorhabditis elegans model for gastrointestinal infection. These results suggest that the intestinal pathogen S. typhimurium can intercept indole signaling from the commensal bacterium E. coli to enhance its antibiotic tolerance in the host intestine.R ather than acting autonomously, bacterial cells communicate with one another to coordinate their efforts and relay vital information. Interspecies and intraspecies bacterial communication has been implicated in many community-dependent behaviors including virulence (1), biofilm formation (2), and antibiotic tolerance (3). Communication may therefore allow control of heterogeneity, which is important in determining fitness of microbial populations (4). Recently, we reported that bacterial communication through indole signaling induces persister formation in Escherichia coli (3). Persistence is an antibiotic-tolerant phenotype in which a dormant subpopulation of cells (persisters) survives antibiotic treatment without having genetically encoded resistance factors (5, 6). In E. coli, we found that indole signaling induced oxidative stress response and phage shock response pathways, thereby increasing the persister frequency within the population. This work suggested that bacteria can use intraspecies signaling to modify the antibiotic tolerance of their population in response to environmental conditions. Indole signaling is used by bacteria in the distal intestine of humans and other mammals (7). In this environment, alkaline and low nutrient conditions induce expression of the indole-producing tryptophanase (tnaA) enzyme in commensal E. coli and related bacteria (8). Indole concentrations in the mammalian intestine (∼300 μM to 1 mM) (9, 10) can induce antibiotic tolerance in E. coli without adversely affecting growth (11). As the mammalian intestine contains a richly m...

Antibiotics and the gut microbiota

“…Microbiotas may recruit other ecosystem members to regain their homeostatic composition, such as phages and the host immune system; furthermore, some species may protect others from antibiotic stress, such as through cell signaling and heterogeneously organized biofilms (67,68). Bacteria have been shown to exhibit cooperative mechanisms of resistance when confronted with antibiotic treatment in vitro (26).…”

Antimicrobial Heteroresistance: an Emerging Field in Need of Clarity

“…Moreover, this E. coli bacterial population may not be truly heteroresistant, owing to the lack of significant variation in concentrations tolerated by its members. Although indole production is not common among bacteria (157), indole produced by E. coli conferred antibiotic resistance to indole-negative Salmonella enterica serovar Typhimurium (158), demonstrating another example of chemical communication. Protection from antibiotics also occurred through antibiotic-degrading enzymes.…”

Staphylococcus aureus Alters Growth Activity, Autolysis, and Antibiotic Tolerance in a Human Host-Adapted Pseudomonas aeruginosa Lineage

“…In relation to microbial infections, it is becoming clear that interactions between bacterial pathogens and other microbial species present at the infection site (either coinfecting pathogens or commensal bacteria) can result in altered pathogen behaviors such as enhanced virulence (1,2), biofilm formation (3), and antibiotic tolerance (4), which may influence disease progression and clinical outcome of the infection. Despite advances in elucidating the molecular details underlying microbial interactive processes, the extent to which evolutionary processes remodel interspecies interactions during the course of infection and therapy is currently not understood.…”