T cell intracellular antigen 1 related protein (TIAR), an RNA-binding protein (RBP), regulates pre-messenger RNA (pre-mRNA) alternative splicing, has been suggested to affect the maturation of primordial germ cells and early mouse embryo development. However, the underlying mechanism remains elusive. In this study, we revealed that TIAR was primarily located in the nucleus at the 2-cell stage embryo, accompanied by highly active transcription. Using immunofluorescence staining and western blotting, we first described the localization and expression level of TIAR during the whole period of oocyte matured and embryogenesis. Knocked down of TIAR could significantly inhibit transcribed and blocked the early mouse embryo development. Combined with RNAP II inhibitor and pre-RNA splicing inhibitor treatment, we further supposed that TIAR might affect transcription at 2-cell via regulating pre-mRNA splicing, and then regulate early mouse embryo development. Collectively, our results provided a novel and potential understanding of TIAR in embryogenesis, suggesting TIAR is required for transcription and embryonic development.

09 Oct 2020·ACS Infectious DiseasesQ2 · MEDICINE

Evaluation of Bacterial RNA Polymerase Inhibitors in a Staphylococcus aureus-Based Wound Infection Model in SKH1 Mice

Q2 · MEDICINE

Article

Author: Röhrig, Teresa ; Bischoff, Markus ; Hartmann, Rolf W. ; Pätzold, Linda ; Murakami, Katsuhiko S. ; Molodtsov, Vadim ; Tschernig, Thomas ; Haupenthal, Jörg ; Kautz, Yannik ; Laschke, Matthias W. ; Hirsch, Anna K. H. ; Elgaher, Walid A. M.

Chronic wounds infected with pathogens such as Staphylococcus aureus represent a worldwide health concern, especially in patients with a compromised immune system. As antimicrobial resistance has become an immense global problem, novel antibiotics are urgently needed. One strategy to overcome this threatening situation is the search for drugs targeting novel binding sites on essential and validated enzymes such as the bacterial RNA polymerase (RNAP). In this work, we describe the establishment of an in vivo wound infection model based on the pathogen S. aureus and hairless Crl:SKH1-Hrhr (SKH1) mice. The model proved to be a valuable preclinical tool to study selected RNAP inhibitors after topical application. While rifampicin showed a reduction in the loss of body weight induced by the bacteria, an acceleration of wound healing kinetics, and a reduced number of colony forming units in the wound, the ureidothiophene-2-carboxylic acid 1 was inactive under in vivo conditions, probably due to strong plasma protein binding. The cocrystal structure of compound 1 with RNAP, that we hereby also present, will be of great value for applying appropriate structural modifications to further optimize the compound, especially in terms of plasma protein binding.

19 Jun 2020·ACS Synthetic BiologyQ2 · BIOLOGY

Bacteriophage Inspired Growth-Decoupled Recombinant Protein Production in Escherichia coli

Q2 · BIOLOGY

Article

Author: Cserjan-Puschmann, Monika ; Striedner, Gerald ; Mairhofer, Juergen ; Feuchtenhofer, Lukas ; Stargardt, Patrick

Modulating resource allocation in bacteria to redirect metabolic building blocks to the formation of recombinant proteins rather than biomass formation remains a grand challenge in biotechnology. Here, we present a novel approach for improved recombinant protein production (RPP) using Escherichia coli (E. coli) by decoupling recombinant protein synthesis from cell growth. We show that cell division and host mRNA transcription can be successfully inhibited by coexpression of a bacteriophage-derived E. coli RNA polymerase (RNAP) inhibitor peptide and that genes overtranscribed by the orthogonal T7 RNAP can finally account to >55% of cell dry mass (CDM). This RNAP inhibitor peptide binds the E. coli RNAP and therefore prevents σ-factor 70 mediated formation of transcriptional qualified open promoter complexes. Thereby, the transcription of σ-factor 70 driven host genes is inhibited, and metabolic resources can be exclusively utilized for synthesis of the protein of interest (POI). Here, we mimic the late phase of bacteriophage infection by coexpressing a phage-derived xenogeneic regulator that reprograms the host cell and thereby are able to significantly improve RPP under industrial relevant fed-batch process conditions at bioreactor scale. We have evaluated production of several different recombinant proteins at different scales (from microscale to 20 L fed-batch scale) and have been able to improve total and soluble proteins yields up to 3.4-fold in comparison to the reference expression system E. coli BL21(DE3). This novel approach for growth-decoupled RPP has profound implications for biotechnology and bioengineering and helps to establish more cost-effective and generic manufacturing processes for biologics and biomaterials.

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