Escherichia coli (E. coli) are mostly harmless bacteria that live in the intestines of animals and humans. They are the most well-studied bacteria and, often, when scientists discover something about E. coli, they extrapolate that discovery across all bacteria. So when scientists learned that E. coli allocates its resources to grow as fast as the environment allows, it was assumed all bacteria behaved similarly.
But researchers at the University of California San Diego have discovered that Bacillus subtilis (B. subtilis), a bacterium commonly found in soil, employs a different survival strategy. The result, published in Science, raises the question of whether other types of bacteria use alternative strategies, and how that knowledge might help researchers think differently about antibiotic tolerance (see Sidebar for more information).
Slower Growth for Better Survival
E. coli grow as fast as conditions allow — sometimes doubling every 20 minutes — so even in adverse conditions, the bacteria continue to multiply as quickly as possible. From an evolutionary point of view, it makes sense: the more E. coli there are, the better the odds that some will survive.
A decade ago, researchers in UC San Diego Professor of Physics Suckjoon Jun's lab set out to reproduce a landmark E. coli result in B. subtilis, and got a surprise. In E. coli, when protein production is partially blocked with an antibiotic, the cell compensates by building even more ribosomes, its protein-making machinery. The team expected B. subtilis to respond the same way. Instead, its ribosome levels stayed flat. Jun assumed they had run the experiment incorrectly, but when the result held up across repeated trials, he realized B. subtilis was managing stress in a fundamentally different way.
To learn more, Jun enlisted the help of Jade Wang, professor of bacteriology at University of Wisconsin-Madison. Wang is an expert on bacterial stringent response, particularly with E. coli and B. subtilis. Stringent response is a survival mechanism used by bacteria to adapt to harsh environmental conditions, such as nutrient deprivation or the presence of antibiotics.
Through their collaboration, Jun realized the two bacteria employ different survival control mechanisms. “Bacteria are generally thought to grow as fast as their available nutrients allow, by carefully balancing how they invest their resources. However, we found that under antibiotic stress, B. subtilis does the opposite, deliberately holding its growth below what it is capable of,” he said.
In order to thrive, bacteria must allocate resources between ribosomes, which build proteins, and the rest of the cell’s components which make the building blocks for those proteins, including amino acids. In E. coli, a small molecule called (p)ppGpp acts like a control switch: when amino acid supplies drop in unfavorable conditions, (p)ppGpp increases and tells the cell to make fewer ribosomes, keeping everything in sync.
B. subtilis has a different control switch, called guanosine triphosphate, or GTP. GTP plays two roles: it powers core processes such as protein synthesis and it acts as a regulatory signal governing functions like the stress response. During adverse environmental conditions, GTP levels in B. subtilis fall. This drop slows the production of amino acids, but the levels of ribosomes stay the same. The result is a decoupling, where the cell’s “factory” is still full of machines, but the supply of raw materials has dwindled.
Keeping the ribosome count steady when GTP drops slows bacteria growth, but also makes it more tolerant of stress. When GTP is high, growth speeds up, but the cells are more vulnerable. This trade‑off lets B. subtilis choose between faster growth and stress resistance depending on environmental conditions.
In experiments by the Jun and Wang labs, B. subtilis was much better at surviving in antibiotic environments than E. coli. This may be related to persistence, in which a small fraction of cells survives antibiotic exposure without becoming genetically resistant, then resume growing once conditions improve.
"We tend to assume bacteria are built to grow as fast as they possibly can. What surprised us is that this one chooses not to. It holds itself back to stay alive under stress, and when we flipped the switch that controls that decision, it grew faster but became far more vulnerable,” stated Jun. “The cell is constantly taking a gamble between growing and surviving, and that gamble may be part of why bacteria are so hard to kill."
The work challenges a longstanding assumption that bacteria are wired simply to grow as fast as possible, showing instead that many balance growth against survival as an active strategy. Because the slowdown is tied directly to antibiotic survival, the findings point to a new way of thinking about how bacteria tolerate antibiotics and survive stress.
Authors include Ryan Thiermann, Aniket Zodage, Taylor Rytlewski, Fangzhou Xiao, John T. Sauls, Sarah Cox, Zulfar Ghulam-Jelani, Victoria Castillo, and Suckjoon Jun (all UC San Diego); Jin Yang, Fukang She, Danny K. Fung, Quinn A. Paulsen, David M. Stevenson, Daniel Amador-Noguez, and Jue D. Wang (all University of Wisconsin-Madison); Farshad Abdollah-Nia and James R. Williamson (both Scripps Research).
This research was funded by the National Science Foundation (1715710), the National Institutes of Health (R35-GM-136412, R35GM127088 and R35GM139622) and the Simons Foundation (SFI-PD-Pivot Fellow-00008375).
Method of Research
Experimental study
Article Title
Decoupling of global metabolic flux and proteome partitioning in bacteria
