Bacterial persistence in humans – treatment

Resistance or persistence?

What is the difference between resistance and persistence? While resistance to antibiotics is caused by mutations and passed on to the bacteria’s offspring, persistence corresponds to a temporary tolerance to antibiotics; the offspring resulting from divisions of these persistent bacteria are in turn susceptible to antibiotics.

This phenomenon was already described by Joseph Bigger in 1944 (Bigger, Lancet, 1944). He observed that penicillin only kills 99% of a staphylococcus culture. Bigger defined the surviving 1% bacteria as “persisters”. These persisters are often in a “dormant” state and do not divide; this is sometimes considered to be the reason why antibiotics are ineffective.

The aim of our work is to identify the host factors that favor the formation of persisters. Recurrent infections often occur in connection with abscesses. Abscesses are characterized by an acidic environment, defined by a low pH value. We investigated the influence of pH on the formation of persisters (Leimer, JID, 2015). In fact, the proportion of persisters was found to be significantly higher under acidic conditions than under pH-neutral conditions.

Treatment

The treatment of abscesses still follows the medical principle “Ubi pus, ibi evacua”, which was written by Hippocrates in ancient times: By surgically removing the pus, a large proportion of the bacteria can be eliminated. However, there are also places in the human body with an acidic pH that cannot be surgically removed.

A human cell (blue) harbors bacteria (green) in the lysosomes (red).

Every human cell has organelles in which acidic conditions prevail, the so-called lysosomes. The function of lysosomes is to break down foreign substances (e.g. bacteria). However, Staphylococcus aureus has the ability to survive in this harsh environment by ceasing growth and entering a dormant state. Human cells can therefore harbor a reservoir of bacteria that cannot be killed by commercially available antibiotics. By modulating the pH of lysosomes, the bacteria are awakened from their sleep and respond again to antibiotic therapy (Leimer, JID, 2015).

These findings should help to further optimize the treatment of chronic Staphylococcus aureus infections and to determine bacterial virulence factors that are largely responsible for recurring infections.

Collaborations

• Prof. Dr. M. Ackermann, Department of Environmental Microbiology
• Prof. Dr. M Loessner, Laboratory for Food Microbiology, ETH Zurich
• Prof. Dr. J. Dworkin, Department of Microbiology & Immunology, Rockefeller University, New York, USA