Mark Brynildsen: Antibiotics that sensitize bacteria to immune attack

The Brynildsen research group has discovered a strategy for making bacteria more susceptible to the body’s own immune system. The strategy could enable the development of new antibiotics that lower bacterial defenses against nitric oxide, a naturally occurring antibacterial agent produced by the body. Such drugs would be less likely to engender resistance because they target bacterial infectivity rather than growth.

Antibiotics that inhibit growth promote resistance everywhere that bacteria encounter the drug, whether in the body or in sewage, soil, water or food. However, drugs that target the infectivity of bacteria limit the pressure to develop resistance to sites of infection inside the body. “When treated with a drug that prohibits infectivity rather than growth, bacteria should take a longer time to develop resistance,” Brynildsen said. “Such drugs also potentially do less harm to beneficial gut bacteria.”

The new strategy involves making bacteria more susceptible to nitric oxide by destroying their defenses against this naturally occurring toxic compound. For Escherichia coli bacteria, some strains of which can cause severe illness and death, these defenses are bolstered by a protein called ClpP and its co-factors ClpA and ClpX.

“We discovered that the ClpP protein and its specificity factors ClpA and ClpX are critically important for E. coli to turn on their nitric oxide defense systems,” Brynildsen said. “Without these proteins, the ability of E. coli to detoxify nitric oxide is compromised.”

The discovery offers a promising anti-infective strategy through the development of small molecule inhibitors of ClpP.