AR-12 Exhibits Direct and Host-Targeted Antibacterial Activity toward Mycobacterium abscessus

Abstract

Therapeutic options for Mycobacterium abscessus infections are extremely limited. New or repurposed drugs are needed. The anti-M. abscessus activity of AR-12 (OSU-03012), reported to express broad-spectrum antimicrobial effects, was investigated in vitro and in vivo. Antimicrobial susceptibility testing was performed on 194 clinical isolates. Minimum bactericidal concentration and time-kill kinetics assays were conducted to distinguish the bactericidal versus bacteriostatic activity of AR-12. Synergy between AR-12 and five clinically important antibiotics was determined using a checkerboard synergy assay. The activity of AR-12 against intracellular M. abscessus residing within macrophage was also evaluated. Finally, the potency of AR-12 in vivo was determined in a neutropenic mouse model that mimics pulmonary M. abscessus infection. AR-12 exhibited high anti-M. abscessus activity in vitro, with an MIC50 of 4 mg/liter (8.7 μM) and an MIC90 of 8 mg/liter (17.4 μM) for both subsp. abscessus and subsp. massiliense. AR-12 and amikacin exhibited comparable bactericidal activity against extracellular M. abscessus in culture. AR-12, however, exhibited significantly greater intracellular antibacterial activity than amikacin and caused a significant reduction in the bacterial load in the lungs of neutropenic mice infected with M. abscessus. No antagonism between AR-12 and clarithromycin, amikacin, imipenem, cefoxitin, or tigecycline was evident. In conclusion, AR-12 is active against M. abscessus in vitro and in vivo and does not antagonize the most frequently used anti-M. abscessus drugs. As such, AR-12 is a potential candidate to include in novel strategies to treat M. abscessus infections.

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“…abscessus ) and G71 ( M. abscessus subsp. abscessus ), in primary mouse peritoneal macrophages ( 16 ). The cells of both the experimental and control groups were washed three times with warm phosphate-buffered saline to remove the extracellular organisms.…”

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“…An antibiotic was considered bactericidal when the MBC/MIC ratio was ≤4; otherwise, it was considered bacteriostatic. 15 …”

Pipeline of anti‐Mycobacterium abscessus small molecules: Repurposable drugs and promising novel chemical entities

“…It was found that its structural analog, OSU‐03012 or AR‐12 (Figure 10), lacks the ability to inhibit cyclooxygenase‐2, but displays a number of other biological effects, including anticancer, antiviral and antibacterial activity 213‐215 . A recent study by Znang et al focused on its anti‐ M. abscessus activity, and the compound was shown to exhibit bactericidal activity with MIC values from 2 to 16 µg/L against 194 clinical M. abscessus isolates 216 . The compound showed an indifferent effect in combination with five antibiotics (clarithromycin, amikacin, imipenem, cefoxitin and tigecycline), that is, the bactericidal rate of the combinations was the same as those of the most active drug in each combination used individually.…”