Engineered particles ‘may become antibiotics of the future’

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.

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 bacteria.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 explains:

“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 pathogen.”

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 future.