Crystal structure of UDP‐N‐acetylglucosamine enolpyruvyl transferase fromHaemophilus influenzaein complex with UDP‐N‐acetylglucosamine and fosfomycin

Abstract

Transfusion‐dependency is associated with poor prognosis in patients with MDS although the causal link for such association is disputed. This study tests thee hypotheses on the association between transfusion burden and prognosis in the MDS: (1) the cumulative transfusion burden is a confounder merely reflecting the time elapsed from diagnosis; (2) it is a surrogate for higher transfusion intensity, which would reflect a more severe disease; and (3) it is the total amount of transfused RBC units that influences on prognosis. We studied 191 transfusion‐dependent patients with MDS or chronic myelomonocytic leukemia. Transfusion intensity was calculated at the time of each transfusion as the yearly‐equivalent number of RBC units. The main outcome was acute leukemia‐free survival from first transfusion. Median transfusion burden was 30 (range: 4–330) RBC units and 112 patients received ≥25 units after a median of 9 months from first transfusion. In nested Cox models, having received ≥25 RBC units had a significant effect on survival (P < 0.001) that was not abrogated by including follow‐up ≥9 months as a time‐dependent covariate. Including transfusion intensity in the model had a significant effect on leukemia‐free survival (P < 0.001) and cancelled the prognostic value of having received ≥25 RBC units. In conclusion, transfusion intensity, instead of the cumulative transfusion burden, is the transfusion‐related variable really influencing on the prognosis of patients with transfusion‐dependent MDS. Am. J. Hematol. 86:245–250, 2011. © 2011 Wiley‐Liss, Inc.

Molecular mechanisms of fosfomycin resistance in clinical isolates of Escherichia coli

“…Inspection of the crystal structure of E. coli MurA complexed with fosfomycin does not suggest an obvious role for Asp-369 and Leu-370 in the protein-inhibitor interaction [24]. However, these amino acids are well conserved among various bacterial species, including Enterobacter cloacae, Haemophilus influenzae, Bacillus subtilis and Staphylococcus aureus [25], suggesting that they are important for the interaction with the substrate phosphoenolpyruvate and its structural analogue fosfomycin. In some natural fosfomycin-resistant organisms, such as Mycobacterium tuberculosis and Chlamydia trachomatis, Asp-115 at the active site of MurA has been identified as conferring resistance [26,27].…”

Cloning, Expression and Characterization of UDP-N-Acetylglucosamine Enolpyruvyl Transferase (MurA) from Wolbachia Endosymbiont of Human Lymphatic Filarial Parasite Brugia malayi

“…The three dimensional model (Figure 10C) was 100% simulated at >90% confidence by using three different bacterial MurA as structure templates viz ., E. coli (PDB: 1UAE) [44], H. influenzae (PDB: 2RL1) [45] and Enterobacter cloacae (PDB: 1EJD) [46] selected by sequence similarity with w Bm-MurA. The Ramachandran plot for a refined w Bm-MurA homology model revealed that 91.9% residues were in the most favored region, 5.5% in the additional allowed region, 2.1% in the generously allowed region and 0.5% in the disallowed region (Figure S2A), thus making the model geometrically acceptable.…”

Resistance to antibiotics targeted to the bacterial cell wall

“…The resulting covalent adduct blocks catalysis, thus reducing the pool of peptidoglycan precursors. Crystal structures of multiple MurA–ligand complexes suggest that the mechanism of inhibition involves flexibility of a loop that lies in close proximity to the active site Cys residue, which can “trap” fosfomycin within the active site cleft …”