Lessons Learnt and the Way Forward for Drug Development AgainstIsocitrate Lyase from Mycobacterium tuberculosis

Abstract: Isocitrate lyase (ICL), an enzyme of the glyoxylate shunt pathway, is essential for the virulence and persistence of dreaded Mycobacterium tuberculosis (Mtb) in its host. This pathway, along with the methylcitrate cycle, facilitates the utilization of fatty acids as a carbon source inside hostile host environments such as in granulomas, and hence enzymes of this pathway are novel antitubercular targets. The genome sequence of pathogenic Mtb H37Rv presents three ICLs annotated as Rv0467 (prokaryotic homologue), Rv1915 and Rv1916. The latter two, Rv1915 and Rv1916, together constitute the longer version of ICL2, a eukaryotic counterpart. Despite being a well-known drug target, no Mtb ICL inhibitor has reached clinical trials due to challenges associated with targeting all the 3 orthologs. This gap is the result of uncharacterized Rv1915 and Rv1916. This review aims to appreciate chronologically the key studies that have built our comprehension of Mtb ICLs. Recently characterized Mtb Rv1915 and Rv1916, which further open venues for developing effective inhibitors against the persistent and drug-resistant Mtb, are discussed separately.