New antibiotic clears chronic infections by forcing bacteria to self-digest

Chronic bacterial infections are extremely difficult to clear completely, even with the best current drugs. Most antibiotics work by disrupting bacterial growth and division. However, there is a small population of infecting cells that adopt a dormant state where they undergo little growth and do not divide. These persistent cells are tolerant to most antibiotics. Antibiotic tolerance is different to resistance because persisters are technically vulnerable to drugs, they are just not expressing the drug targets at the time of treatment. Chronic infections also tend to form biofilms – layers of bacteria stuck to surfaces such as catheters or heart valves – that form a barrier preventing immune cells from accessing all the cells.

A team at Northeastern University in Boston have reported a new compound called ADEP4 that effectively clears chronic infections in combination with a conventional antibiotic. ADEP4 enters bacterial cells and activates an enzyme called ClpP, which breaks down proteins.  Usually, ClpP only digests faulty proteins and requires lots of energy, but ADEP4 holds the catalytic domain open in a way that means it no longer uses energy and its specificity is vastly decreased so it targets over 400 different proteins in the cell. This makes it perfect for killing persisters, which are often energy-starved, essentially by causing the cell to digest itself.

The group found that treating a model of persister cells with ADEP4 alone induced mutants with inactivated ClpP that escaped killing. The combination, however, of ADEP4 and rifampicin, a conventional antibiotic, eradicated the infection to undetectable levels. The results were the same when this combination was tested in a mouse model of a chronic Stapholococcus aureus infection in an immunocompromised patient. These findings are very exciting as they represent a new way of clearing chronic infections and biofilms, which are a breeding ground for antibiotic-resistant strains.

The original article can be found here: http://www.nature.com/nature/journal/vaop/ncurrent/full/nature12790.html