Power naps: ribosome hibernation in bacterial drug targeting and stress tolerance
Lead Research Organisation:
Newcastle University
Department Name: Biosciences Institute
Abstract
When bacteria are assaulted with drugs, they activate various defence mechanisms to stay alive and mitigate drug toxicity. These defence strategies allow pathogenic bacteria to escape clinical treatment, making drug-resistant infections a leading cause of death around the world.
In this project, we will help address the emerging problem of antimicrobial resistance by describing a previously unknown mechanism of resistance known as "Balon-induced ribosome hibernation". In brief, our preliminary studies have identified a new bacterial protein, Balon, that induces a cellular "coma" when bacteria are treated with drugs: during a drug exposure, Balon binds most cellular ribosomes (machines of protein synthesis required for bacterial growth) and converts them into a dormant state, causing arrest of cell growth. When drugs are removed from the media, Balon "awakens" bacterial cells by forcing their ribosomes to reengage in protein synthesis. What's more, our preliminary study shows that Balon is encoded not only by many bacterial genomes but also by plasmids that confer multidrug-resistance in more than 150 clinical and veterinary isolates of pathogenic bacteria, including Salmonella enterica, Pseudomonas aeruginosa, Klebsiella pneumoniae and Escherichia coli.
In this study, the successful student will explore the molecular mechanism of Balon-induced drug resistance.
Aim 1 | Determine the cryo-EM structure of Balon bound to bacterial ribosomes
First, using our established expertise in cryo-EM microscopy (Advisor 1), we will determine the structure of Balon bound to bacterial ribosomes. This structure will reveal the molecular mechanism by which Balon protects ribosomes from antimicrobial drugs (specifically from clinical drugs from aminoglycoside and macrolide families).
Aim 2 | Determine the occurrence of Balon-coding genes in bacteria and their plasmids
Next, using our established expertise in studying the evolution of genomes and plasmids (Advisor 2), we will reveal the distribution of Balon-coding genes across all bacteria and bacterial plasmids with determined genome sequences. This analysis will help to better understand how this drug-resistance factor propagates among bacteria, including pathogens of humans and domesticated animals.
Aim 3 | Determine the physiological conditions that stimulate Balon synthesis in bacterial cells
Finally, using our established expertise in transcriptional studies (Advisor 3), the student will clone promoters of Balon-coding genes into DNA reporters. These reporters will allow us test how hostile environments (such as antibiotics and numerous stress conditions) regulate the expression of Balon. This analysis will help us to test our hypothesis that certain environments predispose bacteria to higher or lower levels of drug resistance.
In this project, we will help address the emerging problem of antimicrobial resistance by describing a previously unknown mechanism of resistance known as "Balon-induced ribosome hibernation". In brief, our preliminary studies have identified a new bacterial protein, Balon, that induces a cellular "coma" when bacteria are treated with drugs: during a drug exposure, Balon binds most cellular ribosomes (machines of protein synthesis required for bacterial growth) and converts them into a dormant state, causing arrest of cell growth. When drugs are removed from the media, Balon "awakens" bacterial cells by forcing their ribosomes to reengage in protein synthesis. What's more, our preliminary study shows that Balon is encoded not only by many bacterial genomes but also by plasmids that confer multidrug-resistance in more than 150 clinical and veterinary isolates of pathogenic bacteria, including Salmonella enterica, Pseudomonas aeruginosa, Klebsiella pneumoniae and Escherichia coli.
In this study, the successful student will explore the molecular mechanism of Balon-induced drug resistance.
Aim 1 | Determine the cryo-EM structure of Balon bound to bacterial ribosomes
First, using our established expertise in cryo-EM microscopy (Advisor 1), we will determine the structure of Balon bound to bacterial ribosomes. This structure will reveal the molecular mechanism by which Balon protects ribosomes from antimicrobial drugs (specifically from clinical drugs from aminoglycoside and macrolide families).
Aim 2 | Determine the occurrence of Balon-coding genes in bacteria and their plasmids
Next, using our established expertise in studying the evolution of genomes and plasmids (Advisor 2), we will reveal the distribution of Balon-coding genes across all bacteria and bacterial plasmids with determined genome sequences. This analysis will help to better understand how this drug-resistance factor propagates among bacteria, including pathogens of humans and domesticated animals.
Aim 3 | Determine the physiological conditions that stimulate Balon synthesis in bacterial cells
Finally, using our established expertise in transcriptional studies (Advisor 3), the student will clone promoters of Balon-coding genes into DNA reporters. These reporters will allow us test how hostile environments (such as antibiotics and numerous stress conditions) regulate the expression of Balon. This analysis will help us to test our hypothesis that certain environments predispose bacteria to higher or lower levels of drug resistance.
Organisations
People |
ORCID iD |
Studentship Projects
| Project Reference | Relationship | Related To | Start | End | Student Name |
|---|---|---|---|---|---|
| BB/T008695/1 | 01/10/2020 | 30/09/2028 | |||
| 2882641 | Studentship | BB/T008695/1 | 01/10/2023 | 30/09/2027 |