Int. J. Antimicrob. Agents (2018) 51: 651-654

Cyclophostin and Cyclipostins analogs, new promising molecules to treat mycobacterial-related diseases

Nguyen, P. C.; Madani, A.; Santucci, P.; Martin, B. P.; Paudel, R. R.; Delattre, S.; Herrmann, J. L.; Spilling, C. D.; Kremer, L.; Canaan, S.; Cavalier, J.-F.

The progression of mycobacterial diseases requires the development of new therapeutics. Here, we evaluated the efficacy and selectivity of a panel of Cyclophostin and Cyclipostins analogs (CyCs) against various bacteria and mycobacteria. The activity of these 26 CyCs was first assayed using the agar plate method. Compounds exhibiting a 50-100% growth inhibition rate were then selected to determine their MIC using the REMA assay. The best drug candidate was further tested against mycobacterial clinical isolates and bacteria responsible for nosocomial infections. These included 6 Gram-negative, 5 Gram-positive bacteria, 29 rapid-growing mycobacteria belonging to the M. chelonae-abscessus clade and 3 slow-growing mycobacteria (Mycobacterium marinum, Mycobacterium bovis BCG, Mycobacterium tuberculosis). Among the 26 CyCs tested, 10 were active and their inhibitory activity was exclusively restricted to mycobacteria. The best candidate, CyC17, further tested on the 26 clinical strains showed a high selectivity for mycobacteria with MIC values (<2 up to 40 µg/mL) comparable to those of most classical antibiotics used to treat M. abscessus infections. Together, these results support the fact that such CyCs represent a new family of potent and selective inhibitors against mycobacteria. This is of particular interest for future chemotherapeutic developments against mycobacterial-associated infections, especially against M. abscessus the most drug-resistant mycobacterial species.