UMN-121

**UMN-121** is a next-generation rifamycin analog designed to overcome resistance mediated by Arr (ADP-ribosyltransferase), which inactivates earlier rifamycins like rifabutin (RBT) by modifying the C23-OH group essential for binding to bacterial DNA-dependent RNA polymerase (RNAP). Developed by researchers at the University of Minnesota and Hackensack Meridian Health, it exhibits potent activity against *Mycobacterium abscessus* (Mab), with MIC of 0.035 µM against wild-type Mab ATCC19977, 0.031 µM against Δarr Mab, and 0.007 µM against *M. tuberculosis* (Mtb). It demonstrates superior efficacy in a GM-CSF−/− mouse model of acute Mab lung infection, reducing lung bacterial burden below detection limits after 7 daily oral doses of 25 mg/kg, outperforming standard four-drug regimens and RBT. Pharmacokinetic properties include oral bioavailability of 56.2%, AUC of 40,339 ng*h/mL at 10 mg/kg, favorable AUC/ssMIC ratios, low metabolic lability, and minimal CYP3A4 induction, positioning it as a preclinical candidate for orally available treatment of drug-resistant nontuberculous mycobacterial pulmonary infections.[1][3][5]