Development of Unprecedented Anti-Tuberculosis Drugs

Stephan Sieber of the Technical University of Munich in Germany will work together with Véronique Dartois of Hackensack Meridian Health in the U.S. to test whether his new antibiotic, which uniquely activates, as well as inactivates, molecular pathways to destroy certain pathogenic bacteria, can be adapted to kill the related Mycobacterium tuberculosis (Mtb), which causes tuberculosis. Current antibiotic treatments are lengthy, and it remains difficult to completely destroy all the bacteria in the body. More worryingly is that Mtb has been developing resistance to these antibiotics, which all work in similar ways, so in some patients they are useless. They have discovered a new antibiotic that works differently: it inactivates bacterial menaquinone biosynthesis but also uniquely activates a signal peptidase to boost its secretory function. In the laboratory, this antibiotic notably bypasses the development of resistance and even kills dormant bacteria, likely by its activating mechanism. They will investigate its mechanism of action in Mtb using affinity-based protein profiling and use that knowledge to select related compounds that might work better in people. These will then be tested in a mouse model of tuberculosis as a first step towards clinical development.