Bacteria Share Proteins to Fight Off Antibiotics

When antibiotics attack bacterial infections, some microbes often persist. The reasons why some bacteria die while their genetically identical counterparts survive have puzzled scientists, but a new study revealed a cunning tool microbes use when exposed to antibiotics: teamwork.

Researchers at Baylor College of Medicine have now shown that bacteria pass proteins to one another at highly accelerated rates when they detect antibiotics, which allows some bacteria to survive.¹ The results, published today in Science, could provide clues for designing better antibiotics.

How Bacteria Beat Antibiotics

Bacteria that survive antibiotic treatment often acquire antibiotic resistance genes to persist, but some use a different approach. “These survivors are not genetically resistant; instead, they temporarily shut down certain parts of their metabolism, entering a dormant-like state that allows them to endure treatment and later regrow,” said Christophe Herman, a microbiologist at Baylor College of Medicine and coauthor of the new study, in a statement. “Understanding how survivors form and remain is a major challenge in fighting persistent infections,” he added.

In persistent bacteria without obvious genetic resistance, the team had previously proposed that bacterial protein sharing might be responsible instead.² In the new study, Herman and his team intended to catch the bacteria red-handed.

“To detect protein transfer, we designed a sensitive system using the bacterium Escherichia coli,” said Alice Wen, a medical scientist in Herman’s lab, in the press release. “We engineered one group of bacteria (donors) to make a special enzyme called Cre, and another group of the same bacteria (recipients) to contain a genetic ‘switch’ that could only flip if Cre protein entered the recipient.”

Using this system, the team tracked whether E. coli could transfer proteins to its neighboring bacteria. Transfers occurred rarely until the bacteria were exposed to antibiotics. In these conditions, protein transfer increased more than 4,000-fold.

How Proteins Help Bacteria Bunker Down

The recipients of this protein transfer showed rapid changes in their physiology. These cells ramped down their own protein production and turned on genes linked to persistence, such as the cell growth inhibitor HipA. “Recipient cells with high HipA activity were more likely to take up protein-carrying vesicles and survive antibiotic treatment,” said Wen.

But antibiotic exposure had an opposite effect on donor cells. These cells fired up a stress response called the phage shock protein (Psp) response, which stimulated the production of tiny bubble-like structures called membrane vesicles that transported proteins to recipient cells. These vesicles could even spread to recipient cells through the liquid supernatant in which donor cells were grown, showing that the process was not dependent on cell-to-cell contact.

In recipients, HipA suppressed the Psp response. These two different responses, said the authors, suggest that antibiotic exposure drives bacteria into adopting either donor or recipient profiles. Recipients are enriched with proteins that help them adopt a persistent state, boosting the chances of bacteria surviving even normally lethal doses of antibiotics.

Identifying these mechanisms could help researchers find a way to stamp out bacterial persisters after antibiotic treatment. Shutting down HipA activity is one potential route. “When HipA was removed, both protein uptake and survival dropped,” said Wen.

The researchers noted that a better understanding of these mechanisms will only come through other studies of the ecological and evolutionary functions of protein transfer among bacteria. Like these pesky bugs, scientists will have to work together to achieve their goal.