MSU-43557

MSU-43557 is an inhibitor and antibacterial agent targeting Mycobacterium abscessus MmpL3, featuring low eukaryotic cytotoxicity, narrow antibacterial spectrum and low drug resistance incidence. It inhibits MmpL3, reduces the content of trehalose dimycolate, interferes with biofilm formation and reduces bacterial activity, and also exerts bactericidal effects on intracellular Mycobacterium abscessus. Combined with antibiotics, it produces additive or synergistic effects, suitable for research on multidrug-resistant strains and related infections of Mycobacterium abscessus.

Methods:
Mycobacterium abscessus, Mycobacterium tuberculosis, Mycobacterium smegmatis, and clinical isolates of multidrug-resistant Mycobacterium abscessus were used as research strains. Gradient concentrations of MSU-43557 were applied for 3 days to evaluate its in vitro antibacterial spectrum, bactericidal activity, and time-dependent bactericidal effect. A mature biofilm model of Mycobacterium abscessus was constructed to detect the ability of the compound to disrupt biofilms and affect the viability of embedded bacteria. A mouse bone marrow-derived macrophage intracellular infection model was established to determine the intracellular bactericidal efficacy and cytotoxicity of MSU-43557.
Results:
1.In vitro experiments showed that MSU-43557 (0.08 nM–80 μM, treatment for 3 days) potently inhibited the proliferation of Mycobacterium abscessus ATCC 19977 and exhibited a time-dependent bactericidal effect at 5-fold the minimum inhibitory concentration. MSU-43557 exerted significant inhibitory effects against Mycobacterium tuberculosis, Mycobacterium abscessus, and Mycobacterium smegmatis, while showing no activity against non-mycobacterial strains within the concentration range of 80 μM. Its antibacterial potency varied among clinical multidrug-resistant Mycobacterium abscessus isolates.
2.MSU-43557 effectively disrupted mature biofilms of Mycobacterium abscessus with a biofilm disruption EC₅₀ of 8.66 μM, and markedly reduced the viability of biofilm-embedded bacteria with an EC₅₀ of 0.16 μM.
3.In the mouse bone marrow-derived macrophage infection model, MSU-43557 efficiently eliminated intracellular Mycobacterium abscessus ATCC 19977 with an intracellular bactericidal EC₅₀ of 0.39 μM. Meanwhile, it displayed low cytotoxicity toward macrophages, indicating favorable biosafety [1].