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Synthesis and Biological Characterization of Fluorescent Cyclipostins and Cyclophostin Analogues: New Insights for the Diagnosis of Mycobacterial-Related Diseases
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Edité par CCSD ; American Chemical Society -
International audience. Patients with cystic fibrosis (CF) have a significantly higher risk of acquiring nontuberculous mycobacteria infections, predominantly due to M. abscessus, than the healthy population. Because M. abscessus infections are a major cause of clinical decline and morbidity in CF patients, improving treatment and the detection of this mycobacterium in the context of a polymicrobial culture represents a critical component to better manage patient care. We report here the synthesis of fluorescent Dansyl derivatives of four active Cyclipostins and Cyclophostin analogs (CyC) and provide new insights regarding the CyC 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 modification of such intracellular localization via disruption of endolysosomal pH strongly affect the CyC accumulation and efficacy. Moreover, we discovered that these fluorescent compounds could became efficient probes to specifically label mycobacterial species with high sensitivity, including M. abscessus in presence several other pathogens like P. aeruginosa and S. aureus. Collectively, all present and previous data emphasized the therapeutic potential of unlabeled CyC, and the attractiveness of the fluorescent CyC as potential new efficient diagnostic tool to be exploited in future diagnostic developments against mycobacterial-related infections, especially against M. abscessus.
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