Cochilimycin B Is a Potential Anti-Mycobacterium marinum Medicine Through Screening the 14-Membered Resorcylic Acid Lactones Library

Mycobacterium marinum can cause disease in both human beings and fishes. Infected fish exhibits symptoms commonly referred to as fish tuberculosis. In this research, we screened a 14-Membered Resorcylic Acid Lactones (RALs) library constructed in the laboratory for in vitro anti- Mycobacterium marinum activity and found that several compounds, including compounds 3 , 4 , 6 , 10 , and 17 – 26 , showed good activity. Notably, the trace natural product cochilimycin B (compound 3 ) possesses significant long-lasting inhibitory function to Mycobacterium marinum . It also shows synergistic effects with drugs like isoniazid, ethambutol, and bedaquiline ( FICI ≤0.5). In addition, cochilimycin B showed a significant inhibitory effect on the biofilm produced by Mycobacterium marinum , with an inhibition rate of 65.9%. To solve the bottleneck problem of natural product drug sources, we realized an efficient one-step semi-synthetic method to obtain compound 3 with a yield of 32.1%. In vivo , inflammatory changes in BALB/c mice infected with Mycobacterium marinum were characterized. After 12 h of infection, IL-1 β was 20%–30% lower in the spleen and tail of the 3 -treated group compared to the control group. In the thymus and tail of the treated group, TNF- α levels were 30%–60% lower than in the control group. This is the first time that the significant anti- Mycobacterium marinum effect of cochilimycin B from 14-Membered Resorcylic Acid Lactones (14-RALs) was reported, offering a new chemical molecule for anti- Mycobacterium marinum drug research.