Authors

Discussion

Benzoxaboroles are a class of bioactive compounds with a broad antimicrobial range. Their high activity against trypanosomes has led to the development of acoziborole, set to become the first single-dose oral treatment for human African trypanosomiasis.

Some compounds belonging to this class are also under evaluation for the treatment of animal African trypanosomosis, or nagana. This livestock disease remains a major cause of poverty and rural underdevelopment in African areas where it is endemic, causing significant economic losses to small-farm holders.

As a novel compound class, unrelated to current veterinary trypanocides, the risk of cross-resistance between benzoxaboroles and commercial trypanocides is low. Selection of resistance to an initial veterinary lead, AN11736, was obtained in vitro. We discovered that trypanosomes become resistant by losing the activity of serine carboxypeptidases (CBPs), which in wild type cells cleave the parental prodrug to a carboxylate derivative that accumulates at high levels. 

We then assessed Trypanosoma brucei and T. congolense resistance and cross-resistance to a series of three benzoxaboroles, all analogues of AN11736. We found that the deletion of the CBP genes was a common feature in the development of resistance in vitro. However, one analogue did not share this profile in T. congolense, suggesting that other molecular mechanisms must be at play for development of resistance to this compound.