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Digestive System Disorders

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CYPA x PPI x PPIB	1

AbstractThe Gram-negative ESKAPE pathogen Pseudomonas aeruginosa is currently listed top of the priority one pathogens by the WHO that require urgent research and development of new antimicrobials. Currently, microbiologists and clinicians face an ever-growing challenge in treating MDR bacterial infections, for this, and other pathogens, using conventional antibiotics. With a limited number of antibiotics currently in clinical trials and a general stagnation in the discovery of promising antimicrobials, new drug targets are desperately needed, and recent investigations include targeting bacterial virulence factors. Targeting bacterial virulence factors should reduce the pathogenesis of an organism, slow its infection progression and prevent vital virulence processes such as biofilm formation as well as potentially increasing a strain’s susceptibility to antibiotics. However, given the incredible diversity of bacteria, virulence mechanisms vary massively, meaning that identifying a broad-spectrum virulence target presents a major challenge. This important point has brought researchers to a fascinating group of enzymes that are ubiquitous in nature, and possess a plethora of biological roles, including acting as virulence factors. The macrophage infectivity potentiators (Mips) belong to the ubiquitous FK506 binding protein (FKBPs) family of peptidyl-prolyl cis/trans isomerases (PPIases). FKBPs are found in all bacteria serving as general house-keeping proteins involved in protein folding and chaperoning. However, a small subset has been identified as virulence proteins. Mips have been characterized in several Gram-negative pathogens including Legionella pneumophila and Burkholderia pseudomallei and were shown to be essential for invasion of macrophages, both in vitro and in murine-infection models, and for other virulence determinants. Pseudomonas aeruginosa also possess three Mip virulence factors, PaMip1, PaMip2 and PaMip3, which are required for the full virulence of P. aeruginosa in in vivo and ex vivo models. Virulence can be addressed in a pharmacological manner using bacterial natural products.

30 Sep 2020·ACM Transactions on Mathematical Software

SODECL

Author: Akman, Ozgur E. ; Lalik, Marta ; Avramidis, Eleftherios

Stochastic differential equations (SDEs) are widely used to model systems affected by random processes. In general, the analysis of an SDE model requires numerical solutions to be generated many times over multiple parameter combinations. However, this process often requires considerable computational resources to be practicable. Due to the embarrassingly parallel nature of the task, devices such as multi-core processors and graphics processing units (GPUs) can be employed for acceleration.Here, we present SODECL (https://github.com/avramidis/sodecl), a software library that utilizes such devices to calculate multiple orbits of an SDE model. To evaluate the acceleration provided by SODECL, we compared the time required to calculate multiple orbits of an exemplar stochastic model when one CPU core is used, to the time required when using all CPU cores or a GPU. In addition, to assess scalability, we investigated how model size affected execution time on different parallel compute devices.Our results show that when using all 32 CPU cores of a high-end high-performance computing node, the task is accelerated by a factor of up to ≈6.7, compared to when using a single CPU core. Executing the task on a high-end GPU yielded accelerations of up to ≈4.5, compared to a single CPU core.

15 Jun 2016·Applied and Environmental Microbiology

An Efficient Method To Generate Gene Deletion Mutants of the Rapamycin-Producing Bacterium Streptomyces iranensis HM 35

Article

Author: Brakhage, Axel A. ; Gregory, Matthew A. ; Leadlay, Peter F. ; Krespach, Mario K. C. ; Flak, Michal ; Schroeckh, Volker ; Netzker, Tina

ABSTRACTStreptomyces iranensisHM 35 is an alternative rapamycin producer toStreptomyces rapamycinicus. Targeted genetic modification of rapamycin-producing actinomycetes is a powerful tool for the directed production of rapamycin derivatives, and it has also revealed some key features of the molecular biology of rapamycin formation inS. rapamycinicus.The approach depends upon efficient conjugational plasmid transfer fromEscherichia colitoStreptomyces, and the failure of this step has frustrated its application toStreptomyces iranensisHM 35. Here, by systematically optimizing the process of conjugational plasmid transfer, including screening of various media, and by defining optimal temperatures and concentrations of antibiotics and Ca2+ions in the conjugation media, we have achieved exconjugant formation for each of a series of gene deletions inS. iranensisHM 35. Among them wererapK, which generates the starter unit for rapamycin biosynthesis, andhutF, encoding a histidine catabolizing enzyme. The protocol that we have developed may allow efficient generation of targeted gene knockout mutants ofStreptomycesspecies that are genetically difficult to manipulate.IMPORTANCEThe developed protocol of conjugational plasmid transfer fromEscherichia colitoStreptomyces iranensismay allow efficient generation of targeted gene knockout mutants of other genetically difficult to manipulate, but valuable,Streptomycesspecies.

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Pipeline

Pipeline Snapshot as of 23 Nov 2024

The statistics for drugs in the Pipeline is the current organization and its subsidiaries are counted as organizations,Early Phase 1 is incorporated into Phase 1, Phase 1/2 is incorporated into phase 2, and phase 2/3 is incorporated into phase 3

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