How persistent bacteria 'sleep' through antibiotic attacks

Swiss researchers have revealed how bacteria can survive antibiotic treatment even without antibiotic resistance by slowing down their metabolism and going into a type of deep sleep, publishing their results in the journal PNAS.

Resistant bacteria evade the effects of antibiotics by becoming less susceptible, for example by breaking the drugs down. But some bacteria have another survival strategy: they withstand treatment by going into a sleep-like state that enables them to tolerate antibiotics. Once therapy is complete, the bacteria wake up and re-establish the infection. This ‘persister’ state can result in recurrent and difficult-to-treat infections, increasing the risk of antibiotic resistance.

Looking to gain new insights into this bacterial population, and funded by the Swiss National Science Foundation, researchers worked with the bacterium Staphylococcus aureus, which is found on the skin of many people and often causes invasive and difficult-to-treat infections. The researchers took bacteria from an infected patient and cultivated them in Petri dishes, where certain bacterial colonies turned out to be smaller than others.

“This tells us that the sample contains persistent bacteria,” said study co-author Professor Annelies Zinkernagel, from the University of Zurich and University Hospital Zurich. “Unlike other bacteria, persistent bacteria must first ‘awaken’, leading to delayed growth in the nutrient medium.” Detection and analysis of persistent bacteria in a patient sample are particularly interesting because most previous studies on persistent bacteria used bacteria that were cultivated over a prolonged period of time in the laboratory and not taken directly from a patient.

To determine the conditions under which bacteria become persistent, the researchers carried out various stress tests. Stress factors include the presence of human immune cells, antibiotics or an acidic environment, as occurs with abscesses. The researchers discovered that the more extreme the stress conditions, the higher the percentage of persistent bacteria.

Using bacteria recently isolated from patients, the researchers also analysed how persistence mechanisms work by looking at the entire set of bacterial proteins, known as the proteome. Their analysis showed that comprehensive molecular reprogramming had taken place and slowed metabolism down in persisters; however, it did not come to a complete standstill, with the bacteria entering a kind of deep sleep. In this way, the bacteria increased their chances of survival in a hostile environment. As soon as the environment becomes more hospitable, the persistent bacteria reverse these changes and again become infectious.

“The idea that bacteria do not halt their metabolism but slow it down and change it is not entirely new; however, it is still controversial. Our study confirms this idea with great precision,” Prof Zinkernagel said. She noted that the current study looked primarily at persistent bacteria, whereas previous experiments were based on mixed populations — “the results may thus have been biased by the other bacteria, which are usually in the majority”.

A better understanding of these mechanisms will contribute to the development of new treatments against persistent bacteria, with the researchers also showing that vitamin A derivatives that target the cell membrane exhibit promising potential for combating less metabolically active bacteria. Alternatively, Prof Zinkernagel said, “If we succeed in reactivating the growth of these bacteria, they would probably no longer be able to evade the antibiotics.”

Image credit: ©stock.adobe.com/au/Kateryna_Kon

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