Nguyen PC

References (6)

Title : Enzymatic synthesis and characterization of maltoheptaose-based sugar esters - Nguyen_2019_Carbohydr.Polym_218_126
Author(s) : Nguyen PC , Nguyen MTT , Lee CK , Oh IN , Kim JH , Hong ST , Park JT
Ref : Carbohydr Polym , 218 :126 , 2019
Abstract : In this study, maltoheptaose (G7)-based sugar esters were synthesized from maltoheptaose and fatty acids (C10-C16) using a commercial lipase. With the exception of dimethyl sulfoxide (DMSO; 76.4%, w/v), G7 showed only limited solubility in organic solvents. Among the fatty acids, palmitic acid (PA) was the best substrate for G7-based ester formation. G7-PA ester was successfully synthesized as the monoester structure exclusively in 10% DMSO of t-butanol with a 22% conversion yield. NMR and enzymatic analyses of the purified monoester product revealed that the ester bond in the G7 was located at C-6 of the glucose at the reducing end. The G7-PA monoester showed the melting temperature at 56.3 degrees C that was 6.5 degrees C lower than that of the free PA and exhibited a different endothermic pattern from the free G7. The G7-PA monoester exhibited excellent emulsifier potential with more even droplet size distribution compared with the commercial sucrose esters for an oil-in-water emulsion system.
ESTHER : Nguyen_2019_Carbohydr.Polym_218_126
PubMedSearch : Nguyen_2019_Carbohydr.Polym_218_126
PubMedID: 31221313

Title : Biochemical and Structural Characterization of TesA, a Major Thioesterase Required for Outer-Envelope Lipid Biosynthesis in Mycobacterium tuberculosis - Nguyen_2018_J.Mol.Biol_430_5120
Author(s) : Nguyen PC , Nguyen VS , Martin BP , Fourquet P , Camoin L , Spilling CD , Cavalier JF , Cambillau C , Canaan S
Ref : Journal of Molecular Biology , 430 :5120 , 2018
Abstract : With the high number of patients infected by tuberculosis and the sharp increase of drug-resistant tuberculosis cases, developing new drugs to fight this disease has become increasingly urgent. In this context, analogs of the naturally occurring enolphosphates Cyclipostins and Cyclophostin (CyC analogs) offer new therapeutic opportunities. The CyC analogs display potent activity both in vitro and in infected macrophages against several pathogenic mycobacteria including Mycobacterium tuberculosis and Mycobacterium abscessus. Interestingly, these CyC inhibitors target several enzymes with active-site serine or cysteine residues that play key roles in mycobacterial lipid and cell wall metabolism. Among them, TesA, a putative thioesterase involved in the synthesis of phthiocerol dimycocerosates (PDIMs) and phenolic glycolipids (PGLs), has been identified. These two lipids (PDIM and PGL) are non-covalently bound to the outer cell wall in several human pathogenic mycobacteria and are important virulence factors. Herein, we used biochemical and structural approaches to validate TesA as an effective pharmacological target of the CyC analogs. We confirmed both thioesterase and esterase activities of TesA, and showed that the most active inhibitor CyC17 binds covalently to the catalytic Ser104 residue leading to a total loss of enzyme activity. These data were supported by the X-ray structure, obtained at a 2.6-A resolution, of a complex in which CyC17 is bound to TesA. Our study provides evidence that CyC17 inhibits the activity of TesA, thus paving the way to a new strategy for impairing the PDIM and PGL biosynthesis, potentially decreasing the virulence of associated mycobacterial species.
ESTHER : Nguyen_2018_J.Mol.Biol_430_5120
PubMedSearch : Nguyen_2018_J.Mol.Biol_430_5120
PubMedID: 30292819
Gene_locus related to this paper: myctu-yt28

Title : Cyclophostin and Cyclipostins analogues, new promising molecules to treat mycobacterial-related diseases - Nguyen_2018_Int.J.Antimicrob.Agents_51_651
Author(s) : Nguyen PC , Madani A , Santucci P , Martin BP , Paudel RR , Delattre S , Herrmann JL , Spilling CD , Kremer L , Canaan S , Cavalier JF
Ref : Int J Antimicrob Agents , 51 :651 , 2018
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 (CyC17) was further tested against 26 clinical strains and showed high selectivity for mycobacteria, with MICs (<2-40 microg/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.
ESTHER : Nguyen_2018_Int.J.Antimicrob.Agents_51_651
PubMedSearch : Nguyen_2018_Int.J.Antimicrob.Agents_51_651
PubMedID: 29241819

Title : Cyclipostins and cyclophostin analogs inhibit the antigen 85C from Mycobacterium tuberculosis both in vitro and in vivo - Viljoen_2018_J.Biol.Chem_293_2755
Author(s) : Viljoen A , Richard M , Nguyen PC , Fourquet P , Camoin L , Paudal RR , Gnawali GR , Spilling CD , Cavalier JF , Canaan S , Blaise M , Kremer L
Ref : Journal of Biological Chemistry , 293 :2755 , 2018
Abstract : An increasing prevalence of cases of drug-resistant tuberculosis requires the development of more efficacious chemotherapies. We previously reported the discovery of a new class of cyclipostins and cyclophostin (CyC) analogs exhibiting potent activity against Mycobacterium tuberculosis both in vitro and in infected macrophages. Competitive labeling/enrichment assays combined with MS have identified several serine or cysteine enzymes in lipid and cell wall metabolism as putative targets of these CyC compounds. These targets included members of the antigen 85 (Ag85) complex (i.e. Ag85A, Ag85B, and Ag85C), responsible for biosynthesis of trehalose dimycolate and mycolylation of arabinogalactan. Herein, we used biochemical and structural approaches to validate the Ag85 complex as a pharmacological target of the CyC analogs. We found that CyC7beta, CyC8beta, and CyC17 bind covalently to the catalytic Ser(124) residue in Ag85C; inhibit mycolyltransferase activity (i.e. the transfer of a fatty acid molecule onto trehalose); and reduce triacylglycerol synthase activity, a property previously attributed to Ag85A. Supporting these results, an X-ray structure of Ag85C in complex with CyC8beta disclosed that this inhibitor occupies Ag85C's substrate-binding pocket. Importantly, metabolic labeling of M. tuberculosis cultures revealed that the CyC compounds impair both trehalose dimycolate synthesis and mycolylation of arabinogalactan. Overall, our study provides compelling evidence that CyC analogs can inhibit the activity of the Ag85 complex in vitro and in mycobacteria, opening the door to a new strategy for inhibiting Ag85. The high-resolution crystal structure obtained will further guide the rational optimization of new CyC scaffolds with greater specificity and potency against M. tuberculosis.
ESTHER : Viljoen_2018_J.Biol.Chem_293_2755
PubMedSearch : Viljoen_2018_J.Biol.Chem_293_2755
PubMedID: 29301937
Gene_locus related to this paper: myctu-a85c

Title : Oxadiazolone derivatives, new promising multi-target inhibitors against M. tuberculosis - Nguyen_2018_Bioorg.Chem_81_414
Author(s) : Nguyen PC , Delorme V , Benarouche A , Guy A , Landry V , Audebert S , Pophillat M , Camoin L , Crauste C , Galano JM , Durand T , Brodin P , Canaan S , Cavalier JF
Ref : Bioorg Chem , 81 :414 , 2018
Abstract : A set of 19 oxadiazolone (OX) derivatives have been investigated for their antimycobacterial activity against two pathogenic slow-growing mycobacteria, Mycobacterium marinum and Mycobacterium bovis BCG, and the avirulent Mycobacterium tuberculosis (M. tb) mc(2)6230. The encouraging minimal inhibitory concentrations (MIC) values obtained prompted us to test them against virulent M. tb H37Rv growth either in broth medium or inside macrophages. The OX compounds displayed a diversity of action and were found to act either on extracellular M. tb growth only with moderated MIC(50), or both intracellularly on infected macrophages as well as extracellularly on bacterial growth. Of interest, all OX derivatives exhibited very low toxicity towards host macrophages. Among the six potential OXs identified, HPOX, a selective inhibitor of extracellular M. tb growth, was selected and further used in a competitive labelling/enrichment assay against the activity-based probe Desthiobiotin-FP, in order to identify its putative target(s). This approach, combined with mass spectrometry, identified 18 potential candidates, all being serine or cysteine enzymes involved in M. tb lipid metabolism and/or in cell wall biosynthesis. Among them, Ag85A, CaeA, TesA, KasA and MetA have been reported as essential for in vitro growth of M. tb and/or its survival and persistence inside macrophages. Overall, our findings support the assumption that OX derivatives may represent a novel class of multi-target inhibitors leading to the arrest of M. tb growth through a cumulative inhibition of a large number of Ser- and Cys-containing enzymes involved in various important physiological processes.
ESTHER : Nguyen_2018_Bioorg.Chem_81_414
PubMedSearch : Nguyen_2018_Bioorg.Chem_81_414
PubMedID: 30212765

Title : Cyclipostins and Cyclophostin analogs as promising compounds in the fight against tuberculosis - Nguyen_2017_Sci.Rep_7_11751
Author(s) : Nguyen PC , Delorme V , Benarouche A , Martin BP , Paudel R , Gnawali GR , Madani A , Puppo R , Landry V , Kremer L , Brodin P , Spilling CD , Cavalier JF , Canaan S
Ref : Sci Rep , 7 :11751 , 2017
Abstract : A new class of Cyclophostin and Cyclipostins (CyC) analogs have been investigated against Mycobacterium tuberculosis H37Rv (M. tb) grown either in broth medium or inside macrophages. Our compounds displayed a diversity of action by acting either on extracellular M. tb bacterial growth only, or both intracellularly on infected macrophages as well as extracellularly on bacterial growth with very low toxicity towards host macrophages. Among the eight potential CyCs identified, CyC 17 exhibited the best extracellular antitubercular activity (MIC50 = 500 nM). This compound was selected and further used in a competitive labelling/enrichment assay against the activity-based probe Desthiobiotin-FP in order to identify its putative target(s). This approach, combined with mass spectrometry, identified 23 potential candidates, most of them being serine or cysteine enzymes involved in M. tb lipid metabolism and/or in cell wall biosynthesis. Among them, Ag85A, CaeA and HsaD, have previously been reported as essential for in vitro growth of M. tb and/or survival and persistence in macrophages. Overall, our findings support the assumption that CyC 17 may thus represent a novel class of multi-target inhibitor leading to the arrest of M. tb growth through a cumulative inhibition of a large number of Ser- and Cys-containing enzymes participating in important physiological processes.
ESTHER : Nguyen_2017_Sci.Rep_7_11751
PubMedSearch : Nguyen_2017_Sci.Rep_7_11751
PubMedID: 28924204
Gene_locus related to this paper: mycle-ML2603 , myctu-a85a , myctu-a85c , myctu-Rv1399c , myctu-Rv2970c , myctu-Rv3569c , myctu-yt28