Tuberculosis (TB) is a treatable disease with the current 6-month regimen of four first-line drugs: isoniazid, rifampicin, ethambutol and pyrazinamide, yet it is the leading cause of death from a single infectious agent and one of the top 10 causes of death worldwide (estimated 1.5 million deaths in 2019) and. While treatment success rate of drug-susceptible TB stays around 85%, treatment for people with rifampicin-resistant TB (RR-TB) and multidrug-resistant TB (MDR-TB) is longer, and requires drugs that are more expensive and more toxic. On top of that COVID-19 pandemic consumed global health resources and disrupted travel to obtain TB diagnoses or treatments, leaving the biggest monster, drug resistant TB, to flourish. Worldwide in 2019, close to half a million people developed RR-TB, of which 78% had MDR-TB. Rifampicin and other rifamycins bind to the β subunit of <i>Mycobacterium tuberculosis</i> RNA polymerase (MTB RNAP) and block RNA synthesis. However, numerous mutations in β subunit of RR-MTB disrupt various key interactions between the rifamycins and the target, leading to minimal to zero drug sensitivity. By taking advantage of the ‘enabling reaction’ of rifamycin core and coupling it with simple click chemistry, we have exploited the broadly-used and thoroughly-studied rifamycin scaffold to target RR-TB and potentially treat other notorious bacterial infections. In this presentation, synthesis, isolation-purification, and biological significance of novel rifamycins with azido, alkyne, and triazole modifications at C8 will be discussed in detail.

Azido, alkyne, and triazole incorporated rifamycin derivatives show promising biological activities

ACS Spring Meeting 2021

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