A Dartmouth study finds that molecular hitchhikers living within bacteria can make their hosts extra resistant to medical treatment by corralling them into tightly packed groups. The findings introduce a previously unknown avenue through which bacterial infections can become more difficult to treat, the researchers say.
DNA molecules called plasmids can hijack host bacteria and force them to grow tube-like appendages called conjugation pili. These tubes latch onto neighboring bacteria, connecting them like the rubberized tunnels between the cars of a passenger train so that copies of the plasmids can pass from one cell to another.
Dartmouth researchers report in Current Biology that as the pili connect cells together, they form dense bacterial clusters that can withstand antibiotics, even if the individual bacteria are not genetically resistant. Plasmids also can force multiple bacterial species into a single community, including those that do not normally form groups.
“These are scary findings,” says Carey Nadell, the study’s senior author and an associate professor of biological sciences. “We’re not seeing antibiotic resistance based on genetic encoding, which commonly happens. Instead, plasmids can make bacterial cells much more tolerant to harm just by changing how they are arranged in space.”
“It’s a simple byproduct of how plasmids move from one cell to the other,” says James Winans, a PhD candidate in Nadell’s lab and the study’s first author. “A lab setting likely makes this process more efficient, but I would be surprised if this weren’t happening in settings outside the laboratory.”
Bacterial communities, or biofilms, are among the most common causes of severe infections, says Nadell, whose group also studies phages, or viruses that kill bacteria. Treatments such as phages and antibiotics usually attack biofilms from the margins and work inward. But cells in the center of a biofilm can evade the assault long enough to multiply and spread infection.
“Clinical treatments for infection are often not very useful against bacteria in a biofilm state,” Nadell says. “Tight bacterial cell groups like our team observed would be difficult to eliminate without extreme measures such as intense heat or bleach, which are obviously not clinically viable treatments.”
The researchers set out to explore how the structure of a biofilm influences the movement of plasmids through bacterial communities. They worked primarily with the intestinal bacterium Escherichia coli and found that a few plasmid carriers introduced to an E. coli biofilm can infect nearly all bacterial cells within three days.
“These are scary findings. … Plasmids can make bacterial cells much more tolerant to harm just by changing how they are arranged in space.”
-Carey Nadell, associate professor of biological sciences at Dartmouth
Plasmids are widespread in nature and cannot remain intact for long periods of time except when inside a bacterial host, Nadell says. For scientists, the simplicity and quick adaptability of plasmids provided an early model for understanding the fundamentals of genetics.
For bacteria, the relationship is give-and-take. “In principle, plasmids can behave as parasites inside bacteria, but some include genetic code that is helpful for their hosts. They confer traits such as the conventional genetic resistance to antibiotics,” Nadell says.
The Dartmouth team’s experiments also show that this super resistance isn’t always useful. “We really enjoy thinking about how these acquired traits can be positive and negative,” Winans says.
While plasmids can help bacteria survive antibiotics, they become worse at other things such as foraging for their next meal, he says.
Bacterial cells forced into clusters become sluggish and slow and unlikely to leave the group, the study finds. “If these dense clusters are forming within patients, that would pose a serious problem,” Winans says.
The clustering effect the team observed in E. coli also occurred between different bacterial species, the researchers report: Salmonella enterica, which is associated with eating undercooked poultry and eggs, and the infection-causing species Serratia fonticola. The team also investigated how growth with other microbes influences plasmid transfer and cluster formation through experiments on the yeast Candida albicans, which lives in the human gut and causes common infections such as thrush, and Vibrio cholerae, which causes the deadly disease cholera.
The researchers plan to explore how the groups created by plasmids promote resistance, Nadell says. The answer could be that bacteria within these biofilms simply become too hard to reach, or that the dense clusters stall cell growth. Many antibiotics only work on cells that are actively growing, he says.
“Plasmids are very common in the natural environment. It’s alarming to think they have an ability to work together with pathogenic bacteria against us and our clinical interventions,” Nadell says. “But it’s better to know that than not to know, and now we can try to find a way around it.”
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