Super-polymers used by gut bacteria to avoid antibiotics

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Gut bacteria exchange drug-resistant DNA and form infectious biofilms more readily than expected.

The discovery shows why it can be so difficult to tackle drug-resistant bacteria, but provides a possible route to tackling the problem. The superpolymer structures that bacteria use to transfer genes could also be exploited for precise drug delivery in future medicine.

Gut bacteria form extracellular appendages called F-pili to connect to each other and transfer bundles of DNA, called genes, that allow them to resist antibiotics. It was thought that the harsh conditions inside human and animal intestines, including turbulence, heat, and acids, would break down the F-pili, making transfer more difficult.

However, new research by a team led by researchers from Imperial College London has shown that F pili are actually stronger under these conditions, helping the bacteria to transfer resistance genes more efficiently and grow. clump together into ‘biofilms’ – protective bacterial consortia – that help repel antibiotics.

The results are published in Nature Communication.

First author Jonasz Patkowski, from Imperial’s Department of Life Sciences, said: “The number of deaths from antimicrobial resistance is expected to match cancer by 2050, which means we need urgent need for new strategies to combat this trend. Much of the spread of resistance is due to the exchange of genes by bacteria, so a detailed understanding of this process could lead to new ways to interrupt it.

Not so fragile

Different classes of bacteria use different types of pili to transfer genes in a process called conjugation. A classic experiment seemed to show that this process was fragile and could be interrupted by agitation, but that left a mystery: why so many bacteria living in harsh conditions like the intestines use these systems if they are so fragile?

The team therefore set out to test this hypothesis. By shaking the E. coli bacteria as they used the F pili during conjugation, they discovered that the shaking actually increased the efficiency of gene transfer between the bacteria. They also observed that after gene transfer, bacteria conjugated under agitated conditions clumped together more easily to form biofilms, which protect the internal bacteria from surrounding antibiotic molecules.

To determine how the F-pili are able to do this, the team subjected them to a resistance test by mounting a bacterium on a stage, connecting a glass bead using “molecular tweezers at the end of one of his F-pili, and pulling. The F-pili turned out to be very elastic, with spring properties that prevented them from breaking.

They also tested the ability of F-pili to resist other common intestinal ailments, subjecting them to sodium hydroxide, urea, and excessively high temperatures of 100°C – at which F- pili survived.

Molecular properties

The team then took it a step further by looking at the F-pili at the molecular level to see what gives them these incredible properties. They are mostly made up of “subunits” of F-pilin with phospholipid molecules bound together.

By modeling the F pili without the phospholipids, the team showed the importance of these molecules for the elasticity and the elastic force of the structure. Repeating the pull experiment revealed that the subunits quickly disassemble without the supporting phospholipids, proving their new role as “molecular glue” in long biopolymers.

Principal Investigator Dr Tiago Costa, from Imperial’s Department of Life Sciences, said: “Making F-pili is very expensive for bacteria in terms of resources and energy, so it’s no surprise they’re worth it. the penalty. We have shown how F-pili accelerate the spread of antibiotic resistance and the formation of biofilms in turbulent environments, but the challenge now is to find ways to combat this very efficient process.

Although it is advantageous to break F pili in pathogenic bacteria, their properties could be useful if we can engineer them for use, for example, in drug delivery. Patkowski explained: “It is difficult to find a tubular appendage with such strong properties. Bacteria use it to transfer genes, but if we could mimic these properties, we could use similar structures to deliver drugs precisely to where they’re needed in the body.

Reference: Patkowski JB, Dahlberg T, Amin H, et al. F-pilus biomechanical adaptability accelerates conjugative diffusion of antimicrobial resistance and biofilm formation. Nat Common. 2023;14(1):1879. do I: 10.1038/s41467-023-37600-y

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