Defining the mechanism of action of the nitrofuranyl piperazine HC2210 against Mycobacterium abscessus.

Mycobacterium abscessus (Mab) has intrinsic resistance to diverse classes of antibiotics, making this non-tuberculous mycobacterial (NTM) infection challenging to treat. Three nitrofuranyl piperazines-HC2209, HC2210, and HC2211-were previously reported to be active against M. tuberculosis (Mtb). Here we report that HC2210 is also active against Mab and define its mechanisms of action. HC2210 is about fivefold more potent than amikacin, is active against multidrug-resistant Mab clinical isolates, and synergizes with bedaquiline, clarithromycin, and meropenem. Isolation of resistant mutants supports that HC2210 requires cofactor F(420), although an F(420-)dependent activating nitroreductase could not be identified. Additionally, resistance mutations in glycerol kinase (glpK) were selected for with HC2210. Transcriptional profiling shows that HC2210 modulates the expression of Mab genes associated with oxidative stress and lipid metabolism, a response that is distinct from Mtb. These findings demonstrate the potential for developing the HC2210 series as a new drug to treat Mab infections.