Indole-2-carboxamides (I2Cs) Target Mycolic Acid Transport and Offer a Potential Treatment for Mycobacterium abscessus and Mycobacterium tuberculosis Infections

Mycobacterium abscessus is a rapidly growing, multidrug-resistant organism, and has emerged as an opportunistic pathogen responsible for an increase in mortality especially in cystic fibrosis (CF) patients. There are limited chemotherapeutic options available for the treatment of infections caused by M. abscessus, mainly because of its resistance to many available antibiotics, including most anti-tubercular drugs. The need for novel and effective chemotherapeutic agents with a novel mode of action cannot be overemphasized. We recently reported that some indole-2-carboxamides (I2Cs) showed potent activity against M. abscessus and M. tuberculosis. Indole-2-carboxamides derivatives showed potent in vitro activity against a range of M. abscessus isolates and in infected macrophages. I2C is efficacious in reducing the count of colony-forming units (CFU) using the tuberculosis aerosol lung infection model in mice. In addition, lead compounds also displayed an acceptable ADME profile. The mode of action of the I2Cs is believed to be associated with the mycolic acid transporter MmpL3 as evidenced by resistance caused by a mutation in the gene encoding for that protein. Biochemical analyses showed that indole-2-carboxamides compounds inhibit the transport of trehalose monomycolate (TMM), causing the loss of trehalose dimycolate (TDM) production and cancelling mycolylation of arabinogalactan, a major structural component of the mycobacterial cell wall. The I2Cs thus represent a new class of chemical structures active against M. abscessus and M. tuberculosis that may offer promise as possible treatment options for M. abscessus infection in CF patients.