A5057698546- Tuberculosis Research and Epidemiology
- Cancer therapeutics and mechanisms
- Mycobacterium research and diagnosis
- Biochemical and Molecular Research
- Pneumocystis jirovecii pneumonia detection and treatment
- Antibiotic Resistance in Bacteria
- Carbohydrate Chemistry and Synthesis
- Microbial Natural Products and Biosynthesis
- RNA and protein synthesis mechanisms
- Bacteriophages and microbial interactions
- Bacterial Genetics and Biotechnology
- Infectious Diseases and Tuberculosis
- Monoclonal and Polyclonal Antibodies Research
- Glycosylation and Glycoproteins Research
- Inhalation and Respiratory Drug Delivery
- X-ray Diffraction in Crystallography
- Force Microscopy Techniques and Applications
- Crystallography and molecular interactions
- Crystallization and Solubility Studies
- Enzyme Structure and Function
- Lipid Membrane Structure and Behavior
- Microbial Inactivation Methods
- Synthesis and biological activity
- DNA and Nucleic Acid Chemistry
- Parasites and Host Interactions
Université de Lille
2014-2025
Inserm
2015-2025
Institut Pasteur de Lille
2014-2025
Center for Infection and Immunity of Lille
2015-2025
Centre National de la Recherche Scientifique
2014-2025
Centre Hospitalier Universitaire de Lille
2016-2025
Institut Pasteur
2000-2023
Université Lille Nord de France
2010-2014
Université Libre de Bruxelles
2011
UCLouvain
1992-2007
Molecular diagnostics are considered the most promising route to achieving rapid, universal drug susceptibility testing for
The anti-tuberculosis drug ethionamide (ETH), which is a structural analog of isoniazid (INH), known to strongly inhibit mycolic acid synthesis in <i>Mycobacterium tuberculosis</i>. Although several targets have been identified for INH, only speculative information available concerning ETH. Mutations within the promoter and coding region enoyl-acyl carrier protein reductase (InhA) were found confer resistance both drugs, thus leading impression that INH ETH may share common mode action....
Although hydrophobic forces are of great relevance in biological systems, quantifying these on complex biosurfaces such as cell surfaces has been difficult owing to the lack appropriate, ultrasensitive force probes. Here, chemical microscopy (CFM) with tips was used measure local organic and live bacteria. On surfaces, we found an excellent correlation between nanoscale CFM macroscale wettability measurements, demonstrating sensitivity method toward hydrophobicity providing novel insight...
Traditionally, cell surface properties have been difficult to study at the subcellular level, especially on hydrated, live cells. Here, we demonstrate ability of chemical force microscopy map hydrophobicity single cells with nanoscale resolution. After validating technique reference surfaces known chemistry, probe local hydrophobic character two medically important microorganisms, Aspergillus fumigatus and Mycobacterium bovis, in relation function. Applicable a wide variety cells, chemically...
Antibiotic resistance is one of the biggest threats to human health globally. Alarmingly, multidrug-resistant and extensively drug-resistant Mycobacterium tuberculosis have now spread worldwide. Some key antituberculosis antibiotics are prodrugs, for which mechanisms mainly driven by mutations in bacterial enzymatic pathway required their bioactivation. We developed drug-like molecules that activate a cryptic alternative bioactivation ethionamide M. tuberculosis, circumventing classic...
Summary Ethionamide (ETH) is an important second‐line antitubercular drug used for the treatment of patients infected with multidrug‐resistant Mycobacterium tuberculosis . Although ETH a structural analogue isoniazid, only little cross‐resistance to these two drugs observed among clinical isolates. Both isoniazid and are pro‐drugs that need be activated by mycobacterial enzymes exert their antimicrobial activity. We have recently identified M. genes, Rv3854c ( ethA ) Rv3855 (ethR ), involved...
The thiourea isoxyl (thiocarlide; 4,4′-diisoamyloxydiphenylthiourea) is known to be an effective anti-tuberculosis drug, active against a range of multidrug-resistant strains Mycobacterium tuberculosis and has been used clinically. Little was its mode action. We now demonstrate that results in dose-dependent decrease the synthesis oleic and, consequently, tuberculostearic acid M. with complete inhibition at 3 μg/ml. Synthesis mycolic also affected. anti-bacterial effect partially reversed by...
This study describes the use and advantages of green fluorescent protein (GFP) as a reporter molecule for mycobacteria. The gfp gene from Aequorea victoria was placed under control hsp60 promoter in shuttle vector pGFM‐11. expression recombinant Mycobacterium smegmatis BCG readily detected on agar plates by development an intense fluorescence upon irradiation with long‐wave u.v. light. In mycobacteria containing pGFM‐11 derivative that lacks promoter, no observed. However, this plasmid...
The emergence of Mycobacterium tuberculosis resistant to first-line antibiotics has renewed interest in second-line antitubercular agents. Here, we aimed extend our understanding the mechanisms underlying para-aminosalicylic acid (PAS) resistance by analysis six genes folate metabolic pathway and biosynthesis thymine nucleotides (thyA, dfrA, folC, folP1, folP2, thyX) three N-acetyltransferase [nhoA, aac(1), aac(2)] among PAS-resistant clinical isolates spontaneous mutants. Mutations thyA...
In many streptococci, competence for natural DNA transformation is regulated by the Rgg-type regulator ComR and pheromone ComS, which sensed intracellularly. We compared ComRS systems of four model streptococcal species using in vitro silico approaches, to determine mechanism ComRS-dependent regulation competence. all investigated, was shown be proximal transcriptional activator expression key genes. Efficient binding strictly dependent on presence (C-terminal ComS octapeptide), contrast...
Tuberculosis (TB) is a leading infectious cause of death worldwide. The use ethionamide (ETH), main second line anti-TB drug, hampered by its severe side effects. Recently discovered "booster" molecules strongly increase the ETH efficacy, opening new perspectives to improve current clinical outcome drug-resistant TB. To investigate simultaneous delivery and booster BDM41906 in lungs, we co-encapsulated these compounds biodegradable polymeric nanoparticles (NPs), overcoming bottlenecks...
We report in this article an extensive structure-activity relationships (SAR) study with 58 thiophen-2-yl-1,2,4-oxadiazoles as inhibitors of EthR, a transcriptional regulator controling ethionamide bioactivation Mycobacterium tuberculosis. explored the replacement two key fragments starting lead BDM31343. investigated potency all analogues to boost subactive doses on phenotypic assay involving M. tuberculosis infected macrophages and then ascertained mode action most active compounds using...
To combat the emergence of drug-resistant strains Mycobacterium tuberculosis, new antitubercular agents and novel drug targets are needed. Phenotypic screening a library 594 hit compounds uncovered two leads that were active against M. tuberculosis in its replicating, non-replicating, intracellular states: 7947882 (5-methyl-N-(4-nitrophenyl)thiophene-2-carboxamide) 7904688 (3-phenyl-N-[(4-piperidin-1-ylphenyl)carbamothioyl]propanamide). Mutants resistant to both harbored mutations ethA...
Abstract Mycobacterium tuberculosis is a successful intracellular pathogen. Numerous host innate immune responses signaling pathways are induced upon mycobacterium invasion, however their impact on M. replication not fully understood. Here we reinvestigate the role of STAT3 specifically inside human macrophages shortly after uptake. We first show that activation mediated by IL-10 and occurs in infected cells as well bystander non-colonized cells. results inhibition IL-6, TNF-α, IFN-γ MIP-1β....
Drug-resistant Mycobacterium tuberculosis (Mtb) remains a major public health concern requiring complementary approaches to standard anti-tuberculous regimens. Anti-virulence molecules or compounds that enhance the activity of antimicrobial prodrugs are promising alternatives conventional antibiotics. Exploiting host cell-based drug discovery, we identified an oxadiazole compound (S3) blocks ESX-1 secretion system, virulence factor Mtb. S3-treated mycobacteria showed impaired intracellular...
Dolichol monophosphomannose (DPM) is an ever-present donor of mannose (Man) in various eukaryotic glycosylation processes. Intriguingly, the related polyprenol (PPM) involved biosynthesis lipomannan and lipoarabinomanan, key bacterial factors termed modulins that are found mycobacteria. Based on similarities to known DPM synthases, we have identified characterized PPM synthase Mycobacterium tuberculosis, now Mt-Ppm1. In present study, demonstrate Mt-Ppm1 possesses unusual two-domain...
Isoxyl (ISO), a thiourea (thiocarlide; 4, 4'-diisoamyloxythiocarbanilide), demonstrated potent activity against Mycobacterium tuberculosis H37Rv (MIC, 2.5 micrograms/ml), bovis BCG 0.5 microgram/ml), avium 2.0 and aurum A+ resulting in complete inhibition of mycobacteria grown on solid media. Importantly, panel clinical isolates M. from different geographical areas with various drug resistance patterns were all sensitive to ISO the range 1 10 microgram/ml. In murine macrophage model,...
Mycobacterial transcriptional repressor EthR controls the expression of EthA, bacterial monooxygenase activating ethionamide, and is thus largely responsible for low sensitivity human pathogen Mycobacterium tuberculosis to this antibiotic. We recently reported structure–activity relationships a series 1,2,4-oxadiazole inhibitors leading discovery potent ethionamide boosters. Despite high metabolic stability, pharmacokinetic evaluation revealed poor mice exposure; therefore, second phase...
Tuberculosis remains a major cause of mortality and morbidity, killing each year more than one million people. Although the combined use first line antibiotics (isoniazid, rifampicin, pyrazinamide, ethambutol) is efficient to treat most patients, rapid emergence multidrug resistant strains Mycobacterium tuberculosis stresses need for alternative therapies. Mycobacterial transcriptional repressor EthR key player in control second-line drugs bioactivation such as ethionamide has been shown...