As antibiotic resistance is growing and posing a threat on public health, developing new antibiotics has become more urgent than ever. Researchers at City University of Hong Kong (CityU) have recently revealed the virulence regulatory mechanism in Pseudomonas aeruginosa, a superbug which is common in patients with a weak immune system and is resistant to many antibiotics. The findings pave ways for identifying good antibiotic targets for new drug development.
Superbug Pseudomonas aeruginosa is a common pathogen of nosocomial infections, causing high morbidity and mortality in immunocompromised patients. It is also naturally tolerant to many clinically important antibiotics such as ampicillin, amoxicillin, and vancomycin.
In 2017, the World Health Organization (WHO) classified this notorious bacterium as one of the three "critical priority pathogens" that new drugs are urgently needed.
A joint research led by Dr Deng Xin (Assistant Professor), a microbiologist, and Dr Wang Xin (Associate Professor), a computational biologist from Department of Biomedical Sciences (BMS) at CityU, have recently revealed the genomic regulatory network in Pseudomonas aeruginosa and identified the master regulators on key pathogenic pathways.
The development of inhibitors against these newly identified master regulators can potentially lead to the discovery of novel drugs that target Pseudomonas aeruginosa.
The findings were published in the latest issue of Nature Communications, titled "An integrated genomic regulatory network of virulence-related transcriptional factors in Pseudomonas aeruginosa".
Finding good antibiotic targets: master regulators
Bacterial pathogenicity is mediated via regulatory networks that include virulence-related transcriptional factors. Transcriptional factors (TFs) are proteins which can turn the specific genes (their functional target genes) "on" and "off", generally a key determinant in whether the gene functions at a given time.
And master regulators are the transcriptional factors that appear to control most of the regulatory activities of other transcriptional factors and the associated genes. Therefore, the master regulators are often good antibiotic targets that can be used for future drug development.
In Pseudomonas aeruginosa, numerous TFs regulate virulence by tuning quorum sensing (QS), the type III secretion (T3SS) and type VI secretion system (T6SS). In the past seven years, in collaboration with Professor Liang Haihua from Northwest University (China), Dr Deng has been working to reveal the pathogenesis of Pseudomonas aeruginosa, and to discover and clarify the regulation mechanism of multiple virulence-related TFs (Shao et al, J Bacteriol, 2018; Zhao et al, PLOS Biol, 2016; Kong et al, Nucleic Acids Res, 2015; Liang et al, Nucleic Acids Res, 2014; Liang et al, J Bacteriol, 2012).
To further conduct a global analysis of the pathogenicity and discover new potential drug targets of Pseudomonas aeruginosa, Dr Deng's team and Dr Wang's team collaborated on the analysis and discovery of the crosstalk - signal pathway affecting another - in the known 20 virulence-related TFs. Subsequently, they mapped the Pseudomonas aeruginosa Genomic regulatory network (PAGnet) to encode the regulatory relationships of these 20 TFs with their functional target genes (Figure 1).
This PAGnet revealed the intricate mechanism of virulence regulation mediated by these TFs and the related crosstalk, and hence led to the identification of nine master regulators, in QS and T3SS.
An online platform for potential wider pathological use
As a contribution to the research community, they have also developed an online platform and R package based on PAGnet to ensure an up-to-date regulatory network and facilitate user-customized analyses (Figure 2). This platform and R package provide network visualization, subnetwork filtering and downloading services to the user, to facilitate the visualization and exploration of the virulence regulatory network, as well as master regulator analysis for the identification of key TFs that mediate a biological process or pathway in Pseudomonas aeruginosa.
"The master regulators we identified are potential antibiotic targets, which has important clinical significance for the development of new antibiotics for Pseudomonas aeruginosa in the future. More importantly, the network we build is not just for Pseudomonas aeruginosa, the methodology and conclusions of this work may be applicable to other bacterial pathogens in the future," commented Dr Deng.
Dr Deng and Dr Wang are the correspondence authors of the paper. The first co-authors are PhD student Huang Hao, Xie Yingpeng and research assistant Dr Shao Xiaolong at CityU's BMS Department. Other authors include PhD student Wang Tingting and research assistant Zhang Yingchao from the Department.
P.K. Lee | EurekAlert!
Quality control in immune communication: Chaperones detect immature signaling molecules in the immune system
20.09.2019 | Technische Universität München
Moderately Common Plants Show Highest Relative Losses
20.09.2019 | Universität Rostock
How long the battery of your phone or computer lasts depends on how many lithium ions can be stored in the battery's negative electrode material. If the battery runs out of these ions, it can't generate an electrical current to run a device and ultimately fails.
Materials with a higher lithium ion storage capacity are either too heavy or the wrong shape to replace graphite, the electrode material currently used in...
To process information, photons must interact. However, these tiny packets of light want nothing to do with each other, each passing by without altering the...
Researchers from the Department of Atomically Resolved Dynamics of the Max Planck Institute for the Structure and Dynamics of Matter (MPSD) at the Center for Free-Electron Laser Science in Hamburg, the University of Hamburg and the European Molecular Biology Laboratory (EMBL) outstation in the city have developed a new method to watch biomolecules at work. This method dramatically simplifies starting enzymatic reactions by mixing a cocktail of small amounts of liquids with protein crystals. Determination of the protein structures at different times after mixing can be assembled into a time-lapse sequence that shows the molecular foundations of biology.
The functions of biomolecules are determined by their motions and structural changes. Yet it is a formidable challenge to understand these dynamic motions.
At the International Symposium on Automotive Lighting 2019 (ISAL) in Darmstadt from September 23 to 25, 2019, the Fraunhofer Institute for Organic Electronics, Electron Beam and Plasma Technology FEP, a provider of research and development services in the field of organic electronics, will present OLED light strips of any length with additional functionalities for the first time at booth no. 37.
Almost everyone is familiar with light strips for interior design. LED strips are available by the metre in DIY stores around the corner and are just as often...
Later during this century, around 2060, a paradigm shift in global energy consumption is expected: we will spend more energy for cooling than for heating....
19.09.2019 | Event News
10.09.2019 | Event News
04.09.2019 | Event News
20.09.2019 | Life Sciences
20.09.2019 | Life Sciences
20.09.2019 | Life Sciences