Intestinal bacteria use super polymers to evade antibiotics

This discovery shows why it is so difficult to overcome drug-resistant bacteria, but provides a possible way to tackle the problem. The super-polymer structures that bacteria use to transfer genes could also be exploited for precise drug delivery in future medicine.

Intestinal bacteria form extracellular appendages called F-pili to connect with each other and transfer packages of DNA, called genes, that enable them to resist antibiotics. It is thought that harsh conditions in the gut of humans and animals, including turbulence, heat, and acid, would break down the F-pili, making transfer more difficult.

However, new research by a team led by Imperial College London researchers has shown that F-pili are actually more resilient under these conditions, helping bacteria transfer resistance genes more efficiently, and clumping into ‘biofilms’ – consortiums of protective bacteria – that help them fend off antibiotics. .

The results are published in Nature Communications.

First author Jonasz Patkowski, from the Department of Life Sciences at Imperial, said: “The death toll from antimicrobial resistance is expected to equal that of cancer by 2050, which means we urgently need new strategies to combat this trend. Much of the spread of resistance is driven by bacteria exchanging genes, so a detailed understanding of this process could lead to new ways to stop it.”

Not so fragile

Different classes of bacteria use different types of pili to transfer genes in a process called conjugation. Classical experiments seem to show that this process is fragile and can be disrupted by agitation, but this leaves a mystery: why do so many bacteria living in harsh conditions such as the gut use this system if they are so fragile?

Therefore the team set out to test this assumption. With shaking E. coli bacteria while they used F-pili during conjugation, they found that agitation actually increased the efficiency of gene transfer between bacteria. They also observed that after gene transfer, conjugated bacteria in the agitated state agglomerate more easily to form biofilms, which protect the inner bacteria from the surrounding antibiotic molecules.

To determine how the F-pili could do this, the team conducted a strength test by mounting the bacteria on a platform, connecting a glass bead using ‘molecular tweezers’ to the end of one of its F-pili, and pulling. F-pili are shown to be highly elastic, with spring-like properties that prevent them from breaking.

They also tested F-pili’s ability to withstand other common gut conditions, by subjecting it to sodium hydroxide, urea, and exorbitant 100°C temperatures – all of which F-pili survived.

Molecular properties

The team then went a step further, looking at F-pili at a molecular level to see what gave them these amazing properties. They mainly consist of F-pilin ‘subunits’ with phospholipid molecules linked together.

By modeling the F-pili without the phospholipids, the team showed how important these molecules are for the malleability and elastic strength of the structure. Repeating the exciting experiment revealed that the subunits quickly disassemble without the phospholipids supporting them, proving their new role as ‘molecular glue’ in long biopolymers.

Lead researcher Dr Tiago Costa, from the Department of Life Sciences at Imperial, said: “Making F-pili is very expensive for the bacteria in terms of resources and energy, so it’s no wonder they’re well worth the effort. We have already shown how F-pili accelerates the spread of antibiotic resistance and biofilm formation in volatile environments, but the challenge now is to find ways to combat this highly efficient process.”

While it would be advantageous to break down F-pili in pathogenic bacteria, its properties could be helpful if we can engineer it for use in, for example, drug delivery. Patkowski explains: “It’s hard to find a tubular appendage with such strong properties. Bacteria use them to transfer genes, but if we can mimic these properties, we can use similar structures to deliver drugs exactly where they are needed in the body.”