We report here the synthesis of fluorescent Dansyl derivatives of four active cyclipostins and cyclophostin analogues (CyCs) and provide new insights regarding the CyC’s lack of activity against Gram-negative and Gram-positive bacteria, and above all into their mode of action against intramacrophagic M. abscessus cells. Our results pointed out that the intracellularly active CyC accumulate in acidic compartments within macrophage cells, that this accumulation appears to be essential for their delivery to mycobacteria-containing phagosomes, and consequently, for their antimicrobial effect against intracellular replicating M. abscessus, and that modifcation of such intracellular localization via disruption of endolysosomal pH strongly affects the CyC accumulation and efcacy. Moreover, we discovered that these fluorescent compounds could become efcient probes to specifcally label mycobacterial species with high sensitivity, including M. abscessus in the presence several other pathogens like Pseudomonas aeruginosa and Staphylococcus aureus. Collectively, all present and previous data emphasized the therapeutic potential of unlabeled CyCs and the attractiveness of the fluorescent CyC as a potential new efficient diagnostic tool to be exploited in future diagnostic developments against mycobacterial-related infections, especially against M. abscessus

Morgane Sarrazin, Benjamin P. Martin, Romain Avellan, Giri Raj Gnawali, Isabelle Poncin, Hugo Le Guenno, Christopher D. Spilling, Jean-François Cavalier, and Stéphane Canaan

Published on 24/11/2022

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