12 research outputs found
Synthesis and Bioactivity of β-Substituted Fosmidomycin Analogues Targeting 1-Deoxy- d
Hamamelitannin analogues that modulate quorum sensing as potentiators of antibiotics against **Staphylococcus aureus**
Synthesis and bioactivity of <tex>\beta$</tex>-substituted fosmidomycin analogues targeting 1-deoxy-D-xylulose-5-phosphate reductoisomerase
Synthesis and Bioactivity of beta-Substituted Fosmidomycin Analogues Targeting 1-Deoxy-D-xylulose-5-phosphate Reductoisomerase
Blocking the 2-C-methyl-d-erythrithol-4-phosphate (MEP) pathway for isoprenoid biosynthesis offers interesting prospects for inhibiting Plasmodium or Mycobacterium spp. growth. Fosmidomycin (1) and its homologue FR900098 (2) potently inhibit 1-deoxy-d-xylulose-5-phosphate reductoisomerase (Dxr), a key enzyme in this pathway. Here we introduced aryl or aralkyl substituents at the beta-position of the hydroxamate analogue of 2. While direct addition of a beta-aryl moiety resulted in poor inhibition, longer linkers between the carbon backbone and the phenyl ring were generally associated with better binding to the enzymes. X-ray structures of the parasite Dxr-inhibitor complexes show that the longer compounds generate a substantially different flap structure, in which a key tryptophan residue is displaced, and the aromatic group of the ligand lies between the tryptophan and the hydroxamates methyl group. Although the most promising new Dxr inhibitors lack activity against Escherichia coli and Mycobacterium smegmatis, they proved to be highly potent inhibitors of Plasmodium falciparum in vitro growth
Structure Guided Lead Generation toward Nonchiral <i>M. tuberculosis</i> Thymidylate Kinase Inhibitors
In
recent years, thymidylate kinase (TMPK), an enzyme indispensable
for bacterial DNA biosynthesis, has been pursued for the development
of new antibacterial agents including against <i>Mycobacterium
tuberculosis</i>, the causative agent for the widespread infectious
disease tuberculosis (TB). In response to a growing need for more
effective anti-TB drugs, we have built upon our previous efforts toward
the exploration of novel and potent <i>Mycobacterium tuberculosis</i> TMPK (<i>Mt</i>TMPK) inhibitors, and reported here the
design of a novel series of non-nucleoside inhibitors of <i>Mt</i>TMPK. The inhibitors display hitherto unexplored interactions in
the active site of <i>Mt</i>TMPK, offering new insights
into structure–activity relationships. To investigate the discrepancy
between enzyme inhibitory activity and the whole-cell activity, experiments
with efflux pump inhibitors and efflux pump knockout mutants were
performed. The minimum inhibitory concentrations of particular inhibitors
increased significantly when determined for the efflux pump <i>mmr</i> knockout mutant, which partly explains the observed
dissonance
RUNX2 regulates leukemic cell metabolism and chemotaxis in high-risk T cell acute lymphoblastic leukemia.
T-cell acute lymphoblastic leukemia (T-ALL) is an aggressive hematologic malignancy with inferior outcome compared to B-cell ALL. Here, we showed that Runt-related transcription factor 2, RUNX2 was upregulated in high-risk T-ALL with KMT2A rearrangements (KMT2A-R) or an immature immunophenotype. In KMT2A-R cells, we identified RUNX2 as a direct target of the KMT2A chimeras, where it reciprocally bound the KMT2A promoter, establishing a regulatory feed-forward mechanism. Notably, RUNX2 was required for survival of immature and KMT2A-R T-ALL cells in vitro and in vivo. We reported direct transcriptional regulation of CXCR4 signaling by RUNX2, thereby promoting chemotaxis, adhesion and homing to medullary and extramedullary sites. RUNX2 enabled these energy-demanding processes by increasing metabolic activity in T-ALL cells through positive regulation of both glycolysis and oxidative phosphorylation. Concurrently, RUNX2 upregulation increased mitochondrial dynamics and biogenesis in T-ALL cells. Finally, as a proof of concept, we demonstrated that immature and KMT2A-R T-ALL cells were vulnerable to pharmacological targeting of the interaction between RUNX2 and its co-factor CBFβ. In conclusion, we showed that RUNX2 acts as a dependency factor in high-risk subtypes of human T-ALL through concomitant regulation of tumour metabolism and leukemic cell migration