Resensitizing bacteria to itaconate as a new approach for the treatment of infections

Although bacteria can cause disease in human (bad bacteria), most do not and can even be beneficial (good bacteria, a.k.a. the microbiome). When harmful bacteria find their way in our body, the immune system is activated and clears the bad bacteria without affecting our microbiome. Occasionally, bacteria overcome our immune defenses, which leads to a bacterial infection and requires medical treatment. Antibiotics are at the basis of modern medicine; they are used not only to cure bacterial infections but also to protect pre-term babies, AIDS patients, as well as patients undergoing chemotherapy, hemodialysis or any surgery. Antibiotics save millions of lives every year. Unlike our immune system, however, antibiotics kill not only the bad bacteria but also affect our microbiome, leading to side effects. Since the discovery of antibiotics and their use in the clinic, we have become locked in an arms race with bacteria: as we develop new antibiotics the bacteria gain resistance to them. Currently, most antibiotics do not work well anymore. We urgently need new antibiotics, but to end the arms race we must find means to treat infections without antibiotics. We propose to replace antibiotics with molecules that make bacteria more susceptible to our immune system, a strategy that will be more selective for bad bacteria and less likely to select for resistance. Notably, we have identified many molecules active in vitro and in a cellular model, some of which have demonstrated efficacy in a mouse model of salmonellosis. We propose here to: 1) test more compounds to identify lead compounds to treat salmonellosis (94 M cases yearly) and tuberculosis (kills >1 million people annually); 2) delineate the pharmacological behavior of our compounds in mice; and 3) start to adapt our approach to Pseudomonas aeruginosa, a bacterium that is highly resistant to antibiotics. We believe that this strategy can revolutionize the treatment of bacterial infections.