The antibiotic resistance crisis is caused, in large part, by the acquisition and exchange of resistance mechanisms by bacteria through genetic mutations. But bacteria find another defense mechanism in the collective behavior of biofilm formation—a structure with a matrix coating that protects the bacteria from environmental insults, including antibiotics. In addition, swarms of bacteria can undergo a phenomenon similar to human traffic jams called “motility-induced phase separation,” in which they slow down when there are large numbers of bacteria crammed together.

Now, researchers from the U.K. have discovered that bacteria undergo a phase transition to form biofilms in response to the presence of an antibiotic. The study reveals how the collective behavior of bacterial colonies may contribute to the emergence of antibiotic resistance. These insights could pave the way to new approaches for treating bacterial infections that help thwart the emergence of resistance.

This work is published in eLife in the paper titled, “Swarming bacteria undergo localized dynamic phase transition to form stress-induced biofilms.”

It is understood, the authors noted, that self-organized multicellular behaviors enable cells to adapt and tolerate stressors. However, how cellular communities alter their collective behaviors adaptively upon exposure to stress is largely unclear.

“In our study, we wanted to see whether swarming bacteria can use physical interactions such as motility-induced phase separation to overcome certain stresses including exposure to antibiotics,” said first author Iago Grobas, a PhD student at Warwick Medical School, University of Warwick, U.K.

In their study, Grobas and colleagues exposed a colony of Bacillus subtilis—a model system for bacterial multicellularity—to the antibiotic kanamycin. When they recorded a time-lapse video of the bacteria’s behavior, the researchers found that the bacteria formed biofilms in the presence of the drug. The team showed that the biofilm forms because bacteria begin to group together a distance away from the antibiotic, giving way to multiple layers of swarming bacteria.

More specifically, swarming bacteria activate matrix genes and transition to biofilms upon exposure to a spatial gradient of kanamycin. The initial stage of this transition, the authors wrote, “is underpinned by a stress-induced multilayer formation, emerging from a biophysical mechanism reminiscent of motility-induced phase separation (MIPS).”

“The layers build up through a physical mechanism whereby groups of cells moving together collide with each other,” Grobas explained. “The collision generates enough stress to pile up the cells, which then move slower, attracting more cells through a mechanism similar to motility-induced phase separation. These multiple layers then lead to biofilm formation.”

The team tested a strategy to stop this formation and thereby prevent antibiotic resistance from occurring in this way. They found that splitting a single dose into two steps without changing the total amount of antibiotics strongly reduced the emergence of a biofilm.

Additionally, the authors found that the physical nature of the process suggests that stressors that suppress the expansion of swarms would induce biofilm formation. In fact, they found that “a simple physical barrier also induces a swarm-to-biofilm transition.”

Further research is needed to determine if bacteria that are harmful to humans use similar behaviors to survive antibiotic exposure. If they do, future treatments should take these behaviors into account in order to reduce antibiotic resistance. The authors proposed a strategy of antibiotic treatment to inhibit the transition from swarms to biofilms by targeting the localized phase transition.

“Our discoveries question the way we use antibiotics and show that increasing the dosage is not always the best way to stop biofilm development,” said co-senior author Munehiro Asally, PhD, associate professor at the school of life sciences, University of Warwick. “The timing of the bacteria’s exposure to drugs is also important.”

“These insights could lead us to rethink the way antibiotics are administered to patients during some infections,” concluded co-senior author Marco Polin, PhD, associate professor at the department of physics, University of Warwick, and a researcher at the Mediterranean Institute for Advanced Studies (IMEDEA), Mallorca.

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