Dying bacteria help the population survive antibiotics

Antibiotics have been used in medical care for about a century. They have greatly improved the treatment of bacterial infections. At the same time, antibiotic resistance has become a global problem. Many antibiotics are also much older than their medical use. Substances such as penicillin evolved in bacteria and other microorganisms over the course of evolution. Many of the mechanisms bacteria use to defend themselves against antibiotics have also existed for millions of years. In the new study, scientists from WUR and the University of Cologne investigated how bacteria of the species Escherichia coli defend themselves against beta-lactam antibiotics. This is the most widely used group of antibiotics, and includes penicillin.

The bacteria studied produce the enzyme beta-lactamase. This enzyme chemically breaks down beta-lactam antibiotics, preventing the antibiotic from working.

Shared senior author Arjan de Visser of the Laboratory of Genetics: “In the experiments, we saw that after an initial growth phase bacterial cultures began to die when they were exposed to the antibiotic. After some time, however, the population recovered and the bacteria continued to grow (see figure 1). This recovery began once the concentration of the antibiotic had fallen below a certain threshold through the action of beta-lactamase.”

The researchers show that the antibiotic concentration falls in two ways. Living bacteria can take up the antibiotic through their cell membrane and break it down inside the cell. In addition, beta-lactamase molecules are released into the surrounding environment when bacterial cells die. These released enzymes also break down the antibiotic.

The quantitative analysis shows that this second route makes an important contribution. The death of some bacteria therefore helps make the environment less harmful for the surviving bacteria. De Visser: “This is a form of collective survival behaviour: individual cells are lost, but in doing so they contribute to the survival of the population.”

The study also shows that not all bacterial populations respond in the same way. The researchers compared two different strains of E. coli. These strains differ strongly in how much cell death contributes to the breakdown of the antibiotic.

That difference matters, because it may also affect how beta-lactamase inhibitors work. These agents are already used in combination with antibiotics. They inhibit the enzyme beta-lactamase, but mainly work outside intact bacterial cells. Populations in which released beta-lactamase plays a larger role are therefore expected to be more sensitive to such inhibitors.

A better understanding of collective survival mechanisms in bacteria is important for ensuring that antibiotics can continue to be used as effectively as possible. The study shows that bacteria do not respond to antibiotics only as individual cells. Processes at population level also determine how well a bacterial culture can recover after exposure to antibiotics.

This insight can help us better understand when combinations of antibiotics and beta-lactamase inhibitors are effective. The research therefore contributes to fundamental knowledge about antibiotic resistance and the search for better treatment strategies.

Read the scientific publication in PNAS.