Biosynthesis and medicinal chemistry of the capuramycin antimycobacterial antibiotics

点击翻译按钮获取中文摘要

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 drug-resistant 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. Furthermore, totally drug-resistant Mtb has now been documented in multiple countries including the United States. The capuramycin family of glycosylated 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 define a biosynthetic mechanism for the assembly of the unusual unsaturated hexuronic acid component in capuramycins (Aim 1) and establish complementary chemical (via neoglycorandomization; Aim 2) and biosynthetic (via native and nonnative glycosyltransferases; Aim 3) platforms for rapidly generating novel hexuronic acid-substituted capuramycins that can be screened for TL1 inhibition, anti-Mtb activity, and improved pharmacological properties. Additionally, these novel capuramycin analogues will be screened as potential substrates or inhibitors of the phosphotransferase CapP, which covalently modifies capuramycin as a strategy of self-resistance within the producing strain and is potentially a widespread resistance mechanism. It is expected that, upon completion of the aims, a new biosynthetic mechanism for sugar incorporation and modification will be defined. Furthermore, the completion of the aims will provide the first practical, comprehensive strategy to rapidly interrogate/modulate the fundamental features of capuramycin core pharmacophore, which will not only be important for the clinical development of capuramycin but can be applied to other glycosylated nucleoside antibiotics, of which dozens are now known with diverse biological activities.