Discovery of Q203, a potent clinical candidate for the treatment of tuberculosis

Tuberculosis kills more than a million people annually, and new treatments are necessary to counter the spread of drug-resistant forms of Mycobacterium tuberculosis . In this issue, Kevin Pethe and his colleagues report their identification of a new antibercular drug, called Q203, that targets the mycobacterial cytochrome bc 1 complex and that showed efficacy in vitro and in vivo . New therapeutic strategies are needed to combat the tuberculosis pandemic and the spread of multidrug-resistant (MDR) and extensively drug-resistant (XDR) forms of the disease, which remain a serious public health challenge worldwide 1 , 2 . The most urgent clinical need is to discover potent agents capable of reducing the duration of MDR and XDR tuberculosis therapy with a success rate comparable to that of current therapies for drug-susceptible tuberculosis. The last decade has seen the discovery of new agent classes for the management of tuberculosis 3 , 4 , 5 , several of which are currently in clinical trials 6 , 7 , 8 . However, given the high attrition rate of drug candidates during clinical development and the emergence of drug resistance, the discovery of additional clinical candidates is clearly needed. Here, we report on a promising class of imidazopyridine amide (IPA) compounds that block Mycobacterium tuberculosis growth by targeting the respiratory cytochrome bc 1 complex. The optimized IPA compound Q203 inhibited the growth of MDR and XDR M. tuberculosis clinical isolates in culture broth medium in the low nanomolar range and was efficacious in a mouse model of tuberculosis at a dose less than 1 mg per kg body weight, which highlights the potency of this compound. In addition, Q203 displays pharmacokinetic and safety profiles compatible with once-daily dosing. Together, our data indicate that Q203 is a promising new clinical candidate for the treatment of tuberculosis.