Transcription-coupled DNA repair underlies variation in persister awakening and the emergence of resistance

Persisters constitute a population of temporarily antibiotic-tolerant variants in an isogenic bacterial population and are considered an important cause of relapsing infections. It is currently unclear how cellular damage inflicted by antibiotic action is reversed upon persister state exit and how this relates to antibiotic resistance development. We demonstrate that persisters, upon fluoroquinolone treatment, accumulate oxidative damage which is repaired through nucleotide excision repair. Detection of the damage occurs via transcription-coupled repair using UvrD-mediated backtracking or Mfd-mediated displacement of the RNA polymerase. This competition results in heterogeneity in persister awakening lags. Most persisters repair the oxidative DNA damage, displaying a mutation rate equal to the untreated population. However, the promutagenic factor Mfd increases the mutation rate in a persister subpopulation. Our data provide in-depth insight in the molecular mechanisms underlying persister survival and pinpoints Mfd as an important molecular factor linking persistence to resistance development.

Intrabronchial application of extracellular histones shows no proinflammatory effects in swine in a translational pilot study

Objective Extracellular histones have been identified as one molecular factor that can cause and sustain alveolar damage and were linked to high mortality rates in critically ill patients. In this pilot study, we wanted to validate the proinflammatory in vivo effects of local histone application in a prospective translational porcine model. This was combined with the evaluation of an experimental acute lung injury model using intrabronchial lipopolysaccharides, which has been published previously. Results The targeted application of histones was successful in all animals. Animals showed decreased oxygenation after instillation, but no differences could be detected between the sham and histone treatments. The histologic analyses and inflammatory responses indicated that there were no differences in tissue damage between the groups.

Intrabronchial Application of Extracellular Histones Shows No Proinflammatory Effects in Swine in a Translational Pilot Study

Objective: Extracellular histones have been identified as one molecular factor that can cause and sustain alveolar damage and were linked to high mortality rates in critically ill patients. In this pilot study, we wanted to validate the proinflammatory in vivo effects of local and systemic histone application in a prospective translational porcine model. This was combined with the evaluation of an experimental acute lung injury model using intrabronchial lipopolysaccharides, which has been published previously.Results: The targeted application of histones was successful in all animals. Animals showed decreased oxygenation after instillation, but no differences could be detected between the sham and histone treatments. Additionally, intravenous histone injection had no effect. The histologic analyses and inflammatory responses indicated that there were no differences in tissue damage between the groups.

Computational study of bacterial depolymerization process of xenobiotic polymer

This study shows an efficient applicability of computational techniques to analyses of microbial depolymerisation process. Microorganisms were cultivated in a culture media in which a polymer was a sole carbon source, and weight distributions before and after cultivation were introduced into inverse analysis for a molecular factor and a time factor of a degradation rate. An inverse problem for two parameter values associated with the time factor was solved numerically. Once the molecular factor and the time factor were given, microbial depolymerization process was simulated.