Engineered particles ‘may become antibiotics of the future’

1 Jul

There is a pressing need for new approaches to fight harmful bacteria as the global threat of rising drug resistance appears set to outpace the rate at which we can produce new

antibiotics to fight deadly infections like tuberculosis.

E. coli
The team has experimented with phagemids designed to kill E. coli and plans to develop a broader range that can kill other harmful bacteria.

Now, researchers in the field of synthetic biology have addressed this challenge

in a different way. They have engineered particles called “phagemids” that enter

targeted harmful bacteria and release toxins that kill them.

Writing in the journal Nano Letters, the team, led by researchers from

the Massachusetts Institute of Technology (MIT) in Cambridge, describe how they

modeled their particles on bacteriophages – viruses that infect and kill


Unlike broad-spectrum antibiotics, bacteriophages target specific bacteria while

leaving friendly bacteria intact. They have been used for many years in various

countries – for instance, in those that were in the former Soviet Union.

But the disadvantage of treatments that use bacteriophages is they can have

harmful side effects, as lead investigator James Collins, an MIT professor of

medical engineering, explains:

“Bacteriophages kill bacteria by lysing the cell, or causing it to

burst. But this is problematic, as it can lead to the release of nasty toxins from

the cell.”

The toxins that are released when the harmful bacteria burst can cause sepsis,

and even death in some cases, he adds. Sepsis is where the infection causes the

immune system to go into overdrive, triggering widespread inflammation, swelling

and blood clotting.

Phagemids infect targeted bacteria with engineered plasmids

In previous work, the team had already engineered bacteriophages that released

proteins that boosted the effectiveness of antibiotics without bursting the
bacterial cells.

For the new study, the researchers developed a particle that works in a similar

way – it targets and kills specific bacteria, without causing the cells to burst

and release their toxins.

They call the particles “phagemids” because they infect the target bacteria with

plasmids – small DNA molecules that can copy themselves inside cells.

Using synthetic biology, the team engineered the plasmids to express proteins

and peptides – short-chain amino acids – that are toxic to the bacterial host

cell. The toxins are designed to disrupt key cell processes such as replication, with

the effect that the bacterial cell dies without bursting.

The team systematically tested a variety of peptides and toxins and

showed how, when some are combined in the phagemids, they kill the great majority

of bacterial cells within a culture.

The method they have developed is highly targeted – it attacks only specific

species of bacteria, which means you can use it to treat an infection without

harming the rest of the microbiome, Prof. Collins explains.

Resistance likely to develop more slowly

The researchers say exposure to the phagemids did not appear to cause the

bacteria to develop any significant resistance, suggesting several rounds of phagemids could be delivered to get a more effective treatment.

Prof. Collins says he expects the bacteria will eventually become resistant, but

probably much more slowly than they would after repeated use of bacteriophages.

He sees the phagemids being used alongside rapid diagnostic tools, currently in

development, that would allow doctors to treat specific infections, and


“You would first run a fast diagnostic test to identify the bacteria

your patient has, and then give the appropriate phagemid to kill off the


The team has experimented with phagemids designed to kill Escherichia coli and

now plans to develop a broader range that can kill pathogens like Clostridium

difficile and Vibrio cholerea – the bacterium that causes cholera.

Alfonso Jaramillo, a professor of synthetic biology at the University of Warwick

in the UK – who was not involved in the research – says the researchers have

created an improved phage therapy that may become the antibiotics of the


Earlier this year, Medical News Today learned how, using a computer

model, researchers identified a simple way to optimize antibiotics dosing that could revive a

whole arsenal of first-line drugs and preserve last-resort antibiotics in the fight

against drug-resistant bacteria.

Written by Catharine Paddock PhD