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.

Cell-Based Therapy for the Treatment of Glioblastoma: An Update from Preclinical to Clinical Studies.

Glioblastoma (GB), an aggressive primary tumor of the central nervous system, represents about 60% of all adult primary brain tumors. It is notorious for its extremely low (~5%) 5-year survival rate which signals the unsatisfactory results of the standard protocol for GB therapy. This issue has become, over time, the impetus for the discipline of bringing novel therapeutics to the surface and challenging them so they can be improved. The cell-based approach in treating GB found its way to clinical trials thanks to a marvelous number of preclinical studies that probed various types of cells aiming to combat GB and increase the survival rate. In this review, we aimed to summarize and discuss the up-to-date preclinical studies that utilized stem cells or immune cells to treat GB. Likewise, we tried to summarize the most recent clinical trials using both cell categories to treat or prevent recurrence of GB in patients. As with any other therapeutics, cell-based therapy in GB is still hampered by many drawbacks. Therefore, we highlighted several novel techniques, such as the use of biomaterials, scaffolds, nanoparticles, or cells in the 3D context that may depict a promising future when combined with the cell-based approach.

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.