Mycobacterium tuberculosis, the main agent of tuberculosis (TB), is responsible for the annual death of 1.5 million people worldwide. Currently, one of the major global concerns is the increasing number of cases of multi drug-resistant tuberculosis (MDR-TB) and extensively drug resistant tuberculosis (XDR-TB) due to the high mortality rate, difficulty of treatment and the high costs involved. Bedaquiline is the only therapeutic option approved by the North American agency Food and Drug Administration (FDA) for treatment of MDR-TB and XDR-TB, however, strains resistant to this drug has already been characterized justifying the need for the discovery of new drugs. Through a phenotypic screening from a library containing more than 5 thousand molecules, we have identified benzofuroxan derivatives with potent anti-TB activity against MTB H37Rv strain and multidrug-resistant clinical isolates, with MIC90 values ranging from 1.44 uM to 62 uM. Moreover, transcriptomic studies revealed that the probable mechanism of action of these compounds occurs through the inhibition of protein synthesis by binding the mycobacterial ribosome. Therefore, in order to optimize this class of compounds and using the molecular modification strategy, we will synthesise two novel series of hybrid compounds which will be evaluated against strains of MTB H37Rv and multidrug-resistant clinical isolates, phenotypically and genotypically characterized. Furthermore, it will also be investigated the likely mechanism and binding site in the ribosome of this new series of molecules through assays using mycobacteriophages and toeprinting. In the present study, it is expected identify new drug candidates for the treatment of multidrug-resistant tuberculosis that could become an alternative to the current anti-TB treatment.
News published in Agência FAPESP Newsletter about the scholarship: