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

Abstract

The progression of mycobacterial diseases requires the development of new therapeutics. This study evaluated the efficacy and selectivity of a panel of Cyclophostin and Cyclipostins analogues (CyCs) against various bacteria and mycobacteria. The activity 26 CyCs was first assayed by the agar plate method. Compounds exhibiting 50-100% growth inhibition were then selected to determine their minimum inhibitory concentrations (MICs) by the resazurin microtiter assay (REMA). The best drug candidate was further tested against clinical mycobacterial isolates and bacteria responsible for nosocomial infections, including 6 Gram-negative bacteria, 5 Gram-positive bacteria, 29 rapid-growing mycobacteria belonging to the Mycobacterium chelonae-abscessus clade and 3 slow-growing mycobacteria (Mycobacterium marinum, Mycobacterium bovis BCG and Mycobacterium tuberculosis). Among the 26 CyCs tested, 10 were active and their inhibitory activity was exclusively restricted to mycobacteria. The best candidate (CyC) was further tested against 26 clinical strains and showed high selectivity for mycobacteria, with MICs (<2-40 µg/mL) comparable with those of most classical antimicrobials 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.

Biochemical and Structural Characterization of TesA, a Major Thioesterase Required for Outer-Envelope Lipid Biosynthesis in Mycobacterium tuberculosis

“…The CyCs are a new class of potent anti-tubercular compounds exhibiting an activity against enzymes with serine or cysteine in their active site [18,19]. We investigated on the ability of CyC17 to efficiently inhibit the enzyme activity of TesA to confirm this enzyme an effective target of the inhibitor.…”

“…We investigated on the ability of CyC17 to efficiently inhibit the enzyme activity of TesA to confirm this enzyme an effective target of the inhibitor. In addition, CyC7β which has been found active against both extracellular and intramacrophagic M. tuberculosis, and CyC6 & CyC8β active on infected macrophages [18,19], were also tested to assess their ability to inhibit TesA activity. Orlistat which has been previously reported as an inhibitor of TesA was used as positive control [33].…”

“…New antibiotics targeting one or more proteins involved in the synthesis of mycobacterial lipids would thus represent a promising way to fight and control TB [9,13]. In this context, monocyclic enolphosphate and phosphonate analogs (CyC) of natural Cyclipostins and Cyclophostin [14][15][16][17] represent a new family of potent and selective inhibitors against mycobacteria only [18]. These CyC analogs act as powerful antitubercular agents affecting growth of M. tuberculosis both in vitro and in infected macrophages with very low toxicity towards mammalian host cells [19].…”

Synthesis of Long‐Chain β‐Lactones and Their Antibacterial Activities against Pathogenic Mycobacteria

“…All 12 new β‐lactone derivatives were tested for their antibacterial activities against the three pathogenic mycobacterial strains using the validated and routine REMA method with the use of resazurin as a marker for bacterial viability to determine their respective MIC 50 values (Table ).…”

“…Many serine/cysteine hydrolases, which are involved in lipid metabolism, play an essential role in cell wall and mycolic acid biosynthesis and maintenance . Therefore, the use of inhibitors of these enzymes to impair such activity is becoming an interesting alternative strategy not only in the fight against TB, but also against other chronic mycobacterial infections like those caused by M. marinum and M. abscessus …”