Biosynthesis and medicinal chemistry of the capuramycin antimycobacterial antibiotics

Tuberculosis (TB)—which is primarily caused by the bacterial pathogen Mycobacterium tuberculosis (Mtb)—is an ancient disease that remains one of the deadliest communicable diseases worldwide. A paramount concern heading into the future is the rapid rise in drugresistant TB. The World Health Organization estimated 480,000 cases of TB with 190,000 deaths in 2014 with resistance to the first-line anti-TB drugs isoniazid and rifampicin. The capuramycin family of nucleoside antibiotics are excellent candidates for anti-TB drug discovery and development because they (i) are considered new chemical entities with several unusual structural features compared to all antibiotics including clinical anti-TB drugs, (ii) target a novel and essential enzyme (translocase 1; TL1) in cell wall biosynthesis, (ii) have exceptional anti-Mtb activity in vitro and in vivo, (iv) are bactericidal and kill Mtb faster than any first-line anti-TB drug in vitro, and (v) have no toxicity. Our primary objectives in this proposal are to (i) define a biosynthetic mechanism for the assembly of the unusual unsaturated hexuronic acid component in capurmaycins and (ii) establish complementary chemical (via neoglycorandomization) and biosynthetic (via native and nonnative glycosyltransferases) platforms for rapidly generating novel hexuronic acid-substituted capuramycins that can be screened as TL1 inhibitors and for anti-Mtb activity. Additionally, this library of analogues will be screened as potential substrates or inhibitors of the capuramycin phosphotransferase CapP, which covalently modifies capuramycins as a strategy of self-resistance within the producing strain.