Probiotic Escherichia coli Nissle 1917 inhibits bacterial persisters that survive fluoroquinolone treatment.

AIMS: Bacterial persisters are rare phenotypic variants in clonal bacterial cultures that can endure antimicrobial therapy and potentially contribute to infection relapse. Here, we investigate the potential of leveraging microbial interactions to disrupt persisters as they resuscitate during the post-antibiotic treatment recovery period. METHODS AND RESULTS: We treated stationary-phase E. coli MG1655 with a DNA-damaging fluoroquinolone and co-cultured the cells with probiotic E. coli Nissle following antibiotic removal. We found that E. coli Nissle reduced the survival of fluoroquinolone persisters and their progeny by over three orders of magnitude within 24 h. Using a bespoke H-diffusion cell apparatus that we developed, we showed that E. coli Nissle antagonized the fluoroquinolone-treated cells in a contact-dependent manner. We further demonstrated that the fluoroquinolone-treated cells can still activate the SOS response as they recover from antibiotic treatment in the presence of E. coli Nissle and that the persisters depend on TolC-associated efflux systems to defend themselves against the action of E. coli Nissle. CONCLUSION: Our results demonstrate that probiotic bacteria, such as E. coli Nissle, have the potential to inhibit persisters as they resuscitate following antibiotic treatment. SIGNIFICANCE AND IMPACT OF THE STUDY: Bacterial persisters are thought to underlie chronic infections and they can lead to an increase in antibiotic-resistant mutants in their progenies. Our data suggest that we can leverage the knowledge we gain on the interactions between microbial strains/species that interfere with persister resuscitation, such as those involving probiotic E. coli Nissle and E. coli MG1655 (a K-12 strain), to bolster the activity of our existing antibiotics.

The AcrAB-TolC Efflux Pump Impacts Persistence and Resistance Development in Stationary-Phase Escherichia coli following Delafloxacin Treatment.

Bacteria have a repertoire of strategies to overcome antibiotics in clinical use, complicating our ability to treat and cure infectious diseases. In addition to evolving resistance, bacteria within genetically clonal cultures can undergo transient phenotypic changes and tolerate high doses of antibiotics. These cells, termed persisters, exhibit heterogeneous phenotypes; the strategies that a bacterial population deploys to overcome one class of antibiotics can be distinct from those needed to survive treatment with drugs with another mode of action. It was previously reported that fluoroquinolones, which target DNA topoisomerases, retain the capacity to kill nongrowing bacteria that tolerate other classes of antibiotics. Here, we show that in Escherichia coli stationary-phase cultures and colony biofilms, persisters that survive treatment with the anionic fluoroquinolone delafloxacin depend on the AcrAB-TolC efflux pump. In contrast, we did not detect this dependence on AcrAB-TolC in E. coli persisters that survive treatment with three other fluoroquinolone compounds. We found that the loss of AcrAB-TolC activity via genetic mutations or chemical inhibition not only reduces delafloxacin persistence in nongrowing E. coli MG1655 or EDL933 (an E. coli O157:H7 strain), but it limits resistance development in progenies derived from delafloxacin persisters that were given the opportunity to recover in nutritive medium following antibiotic treatment. Our findings highlight the heterogeneity in defense mechanisms that persisters use to overcome different compounds within the same class of antibiotics. They further indicate that efflux pump inhibitors can potentiate the activity of delafloxacin against stationary-phase E. coli and block resistance development in delafloxacin persister progenies.

The social network: Impact of host and microbial interactions on bacterial antibiotic tolerance and persistence.

Antibiotics have vastly improved our quality of life since their discovery and introduction into modern medicine. Yet, widespread use and misuse have compromised the efficacy of these compounds and put our ability to cure infectious diseases in jeopardy. To defend themselves against antibiotics, bacteria have evolved an arsenal of survival strategies. In addition to acquiring mutations and genetic determinants that confer antibiotic resistance, bacteria can respond to environmental cues and adopt reversible phenotypic changes that transiently enhance their ability to survive adverse conditions, including those brought on by antibiotics. These antibiotic tolerant and persistent bacteria, which are prevalent in biofilms and can survive antimicrobial therapy without inheriting resistance, are thought to underlie treatment failure and infection relapse. At infection sites, bacteria encounter a range of signals originating from host immunity and the local microbiota that can induce transcriptomic and metabolic reprogramming. In this review, we will focus on the impact of host factors and microbial interactions on antibiotic tolerance and persistence. We will also outline current efforts in leveraging the knowledge of host-microbe and microbe-microbe interactions in designing therapies that potentiate antibiotic activity and reduce the burden caused by recurrent infections.