Harvard Scientists Explore How Plasmid Rivalries Inside Bacteria Could Help Fight Antibiotic Resistance

Researchers from the Blavatnik Institute at Harvard Medical School have introduced a surprisingly fresh angle in the global fight against antibiotic resistance. Their new study shows that tiny genetic elements called plasmids, which play a huge role in making bacteria antibiotic-resistant, also compete with each other inside bacterial cells. And understanding this microscopic rivalry could open the door to new strategies that weaken or even eliminate antibiotic-resistance traits before they spread.

This work, led by Fernando Rossine along with Michael Baym and Johan Paulsson, has been published in Science. The project tackles a long-standing mystery: how plasmids evolve inside individual bacteria, especially at the earliest moments when two different plasmids must share the same cellular space. Scientists have suspected for years that intracellular plasmid competition likely shapes the evolution of antibiotic resistance, but up until now, actually watching this competition unfold in real time was nearly impossible.

Below is a clear breakdown of what the researchers discovered, how they did it, and why it matters — followed by helpful background info to give readers a fuller understanding of plasmids and antibiotic resistance.

How the Study Was Done

One of the biggest challenges in studying plasmid behavior is simply getting the experiment started on equal footing. To solve this, the research team designed a setup where every bacterial cell began with equal numbers of two different plasmids. These plasmids were designed to compete directly with each other inside the same cell.

The next hurdle was whether they could track this competition without interference from the surrounding colony of bacteria. To handle this, the team used microfluidic devices, which allowed them to isolate single bacterial cells. Inside these tiny chambers, the researchers could precisely observe how plasmids replicated, how they passed on to daughter cells, and which ones eventually dominated.

Through this fine-grained setup, they were able to collect detailed insights into plasmid replication rates, stability, and “fitness.” In simple terms, they could see which plasmid variants were better at surviving, copying themselves, and sticking around as the bacterial cell divided.

What the Researchers Discovered

Here are the main findings, explained clearly and without skipping any of the important details:

• Plasmids evolve independently of a bacterium’s chromosomes, even though they live inside the same cell.
• They are also major drivers of antibiotic resistance, because they can move between bacteria easily — even across species.
• When two plasmids exist inside the same cell, they compete for replication resources. This competition can influence which plasmid becomes dominant and which gets lost as cells divide.
• The study revealed that plasmids do not simply evolve based on external pressures such as antibiotics. Instead, their evolution is also shaped by constraints inside the cell itself.
• The team observed that plasmids with lower gene expression, meaning those that are not heavily transcribing their genes, tend to win in this internal competition. This is interesting because it means plasmids that carry many extra genes — including resistance genes — might sometimes be at a disadvantage if those genes impose extra metabolic cost.
• These internal evolutionary limits could potentially be used against plasmids. If scientists can figure out ways to amplify or manipulate plasmid competition, they might encourage plasmids to lose resistance genes or prevent them from maintaining them.

The big idea is that plasmids aren’t just passively carrying resistance traits. They’re constantly wrestling with each other, and this struggle can shape the spread of antibiotic resistance in ways we haven’t fully understood until now.

Why This Research Matters

Antibiotic resistance is one of the most dangerous health threats of our time, killing an estimated 1.3 million people every year around the world. Plasmids are the main reason resistance can spread so fast, because they act like tiny genetic delivery drones that transfer resistance genes between bacteria.

Most strategies for fighting antibiotic resistance focus on:

• developing new antibiotics
• restricting antibiotic usage
• disinfecting environments
• controlling infections in hospitals

But this new research suggests another pathway: targeting the plasmids themselves by exploiting their natural weaknesses.

If plasmids must battle each other inside cells, and if we now know the rules of that competition, then scientists may be able to push plasmids into evolutionary traps. For example:

• encouraging plasmids to lose resistance genes
• destabilizing plasmids so bacteria can’t maintain them
• manipulating plasmid replication so the harmful ones get outcompeted naturally

This is a fresh and potentially powerful perspective — one that uses evolution against antibiotic resistance rather than trying to fight it head-on.

Understanding Plasmids: A Quick Primer

To fully appreciate this study, it helps to understand what plasmids are and why they matter.

What Exactly Are Plasmids?

Plasmids are small, circular DNA molecules found in bacteria. They:

• replicate independently of the bacterial chromosome
• can carry beneficial genes
• can transfer between bacteria, even unrelated species
• are often responsible for antibiotic resistance genes

Unlike chromosomes, plasmids aren’t essential for bacterial survival. But they often give bacteria important advantages — such as resisting antibiotics, digesting new food sources, or producing toxins.

Why Do Plasmids Spread Resistance?

Plasmids excel at sharing genes. Through processes like conjugation, they can move from one bacterium to another. If a plasmid carries a resistance gene for an antibiotic, any bacterium that receives that plasmid becomes resistant too.

This is why resistance can spread so quickly in hospitals, wastewater systems, farms, and natural environments.

Why Don’t Plasmids Always Keep Their Resistance Genes?

Carrying extra genes is expensive for bacteria. Resistance genes, especially those that are highly expressed, can slow down growth. If there’s no antibiotic around, bacteria often do better without these genes — but plasmids sometimes keep them anyway because they spread so easily.

The new study shows that internal plasmid competition can influence whether plasmids keep or discard such genes. That makes plasmid-plasmid interactions an appealing new target for intervention.

How This Study Changes the Bigger Picture

Scientists have long understood the role of plasmids in spreading resistance, but have mostly focused on how plasmids move between bacteria. This new work emphasizes the importance of what happens inside a single cell.

In this internal arena:

• plasmids compete
• plasmids evolve
• plasmids shape each other’s survival
• and their competition influences the long-term spread of resistance traits

By revealing new constraints on plasmid evolution, the Harvard team has opened the door to new types of therapies — therapies that might someday weaken resistance not by killing bacteria, but by redirecting the evolution of the plasmids that empower them.

Research Paper Link

Intracellular competition shapes plasmid population dynamics — Science (2025)
https://www.science.org/doi/10.1126/science.adx0665