Aviation safety may provide useful lessons Champions of inclusive innovation Researchers from the Yong Loo Lin School of Medicine, National University of Singapore (NUS Medicine) have joined forces with University of California, Berkeley (UC Berkeley). Collectively, they have developed a pioneering method known as Dual transposon sequencing (Dual Tn-seq). This cutting-edge technique allows scientists to rapidly map genetic interactions across bacterial cells. Importantly, it opens up new, exciting opportunities to push the frontier on advancing antibiotic development.
Dual Tn-seq uses a molecular “matchmaker” enzyme known as Cre recombinase to create cells that have two random transposon insertions. This strategy allows researchers to test complex genetic interactions more easily in bacteria, especially in Streptococcus pneumoniae, an important community-acquired respiratory pathogen. This kicker makes this bacterium an excellent genetic model. Its wealth of genetic information and the relative ease of manipulating it in the lab makes for some really powerful experiments.
To conduct their research, the team targeted Streptococcus pneumoniae’s 1.3 million potential gene-pair deletions, a process that massively extended the available genetic toolbox. Their results revealed 244 important gene interactions, that included deadly combinations. When the team deleted both genes in the bacteria, this resulted in bacterial cell death. This integrative, fine-grained mapping of interactions provides new knowledge about bacterial genetics that may be key to designing next-generation antibiotics.
Advancements in Genetic Research
The introduction of Dual Tn-seq also represents an important development in genetic research methods. This new experimental method provides an opportunity for scientists to study the interactions between genes together at the same time instead of separately. Doing such research the old-fashioned way — testing one gene at a time — can be a time-consuming and grueling process. Moreover, these investigative approaches often result in ambiguous findings from gene redundancy, with different genes often taking on the same functions.
“By looking at pairs of genes instead of just one at a time, we can uncover hidden weaknesses in bacteria that would otherwise go unnoticed,” – Professor Adam Deutschbauer
This new Cumseq capability offers a powerful new lens onto the genetic blueprints of bacterial life, uncovering essential relationships between genes. This research holds groundbreaking implications beyond fundamental biology. It opens the door for breakthrough antibiotic approaches to combating dangerous, drug-resistant infections.
Insights into Bacterial Functionality
With this technology, the research team was able to functionalize 67 previously enigmatic proteins. They focused on revealing potential protein functions by identifying interactions with well-studied genes. One of those initial discoveries was the protein YjbK, which acts as a kind of “starter switch” for constructing the bacterial cell wall. This surprising finding not only increases our understanding of bacterial biology, but points to a wealth of possible targets for antibiotic intervention.
“This is like mapping the social network for [bacterial genes],” – Assistant Professor Chris Sham Lok To
Mapping these interactions between various bacterial genes paints a useful picture for understanding how these microbes operate and thrive. In the end, learning how to manipulate such relationships will be key to designing more powerful countermeasures to bacterial infections.
Implications for Antibiotic Development
The results of this study have significant consequences for the future state of antibiotic innovation. Yet with bacterial resistance to current drugs on the rise, the need for new targets for intervention is more important than ever.
“We can now see which genes depend on each other, and which pairs of genes bacteria can’t live without. That’s exactly the insight we need for next-generation antibiotics,” – Assistant Professor Chris Sham Lok To
Already, the team’s findings have uncovered hundreds of unrecognized vulnerabilities lurking inside bacterial genomes. These vulnerabilities can be manipulated to develop novel therapeutic interventions. As they unravel more of these genetic interactions, the odds of stumbling upon a novel antibiotic increase immensely.