How bacteria outsmart antibiotics

Pathogenic bacteria can survive in the body despite antibiotic treatment. They do so in two ways: firstly, pathogens that are genetically resistant to the agent survive; secondly, bacteria are able to alter their behaviour and outsmart antibiotics non-genetically, which scientists refer to as persistence. Although genetic resistance to antibiotics has been studied extensively, we still know very little about persistence.

Slow-growing bacteria

Scientists from ETH Zurich have now put this bacterial survival strategy under the microscope. In experiments on mice, which they had infected with Salmonella, and using mathematical modeling, they discovered how persistence develops: in the course of a bacterial infection, the immune system¡¯s sentinel cells (dendritic cells) engulf a fraction of the pathogens and trigger an immune response. What fundamentally helps the body to combat the pathogens, however, also has a major drawback from a medical point of view: in the special environment inside the sentinel cells, a proportion of the trapped bacteria stop multiplying rapidly. ¡°Instead, they merely loiter about,¡± says Wolf-Dietrich Hardt, a professor of microbiology and project supervisor, with a grin. Antibiotics are practically non-functional against these slow-growing bacteria.

The researchers infected mice with Salmonella and treated them with ciprofloxacin, a commonly used broad-spectrum antibiotic. They isolated sentinel cells from lymph nodes in the gut and discovered surviving Salmonella within them. They then conducted tests to determine the bacteria¡¯s replication rate and susceptibility to the antibiotic and compared them with Salmonella from the mouse gut.

It turned out that the Salmonella from the sentinel cells and the gut included both the fast-growing variety that had been killed off by the antibiotic and their slow-growing counterparts, against which ciprofloxacin was ineffective. The proportion of slow-growing, antibiotic-tolerant bacteria in the lymph node¡¯s sentinel cells, however, was several times higher.

Response to low-nutrient conditions

The reason for this is not that sentinel cells have a propensity for absorbing slow-growing bacteria, as the experiments revealed. Much rather, the Salmonella inside the sentinel cells altered their reproductive behaviour, presumably in response to the prevalent low-nutrient conditions there.

Analysing the experimental data, Roland Regoes, a scientist at the Institute of Theoretical Biology, also managed to demonstrate that the bacteria¡¯s replication rate in the lymph nodes plummeted during the antibiotic treatment. This is down to the fact that the fast-dividing bacteria are killed off by the antibiotic, which leads to an accumulation of slow-growing bacteria in the lymph nodes.

Infection can flare up again

Persistent bacteria can transform back into quick-growing pathogens during an attack, which means that the infection can flare up again after the course of antibiotics has ceased. This is why ciprofloxacin ¨C like other antibiotics ¨C usually have to be taken for several days, despite the fact it starts working within hours or even minutes, says Hardt.

The ETH-Zurich scientists can envisage several approaches towards tackling persistence and increasing the impact of antibiotics. In their study, the researchers revealed that the sentinel cells can be coaxed into eliminating persistent bacteria with particular agents. Hardt, however, even talks about additional approaches: ¡°If we had a drug that shook the persistent bacteria out of their slumber and transformed them into fast-growing ones ¨C which respond to antibiotics ¨C we could combine it with an antibiotic.¡± Or a drug could be sought that specifically kills off persistent bacteria. There are currently no substances for the latter two approaches. If pharmaceutical chemists ever discover any, however, their efficacy could be tested with their experiments, as the ETH-Zurich scientists point out.