A review on the mechanistic details of OXA enzymes of ESKAPE pathogens.

The production of ß-lactamases is a prevalent mechanism that poses serious pressure on the control of bacterial resistance. Furthermore, the unavoidable and alarming increase in the transmission of bacteria producing extended-spectrum ß-lactamases complicates treatment alternatives with existing drugs and/or approaches. Class D ß-lactamases, designated as OXA enzymes, are characterized by their activity specifically towards oxacillins. They are widely distributed among the ESKAPE bugs that are associated with antibiotic resistance and life-threatening hospital infections. The inadequacy of current ß-lactamase inhibitors for conventional treatments of 'OXA' mediated infections confirms the necessity of new approaches. Here, the focus is on the mechanistic details of OXA-10, OXA-23, and OXA-48, commonly found in highly virulent and antibiotic-resistant pathogens Acinetobacter baumannii, Klebsiella pneumoniae, Pseudomonas aeruginosa, and Enterobacter spp. to describe their similarities and differences. Furthermore, this review contains a specific emphasis on structural and computational perspectives, which will be valuable to guide efforts in the design/discovery of a common single-molecule drug against ESKAPE pathogens.

How Epstein-Barr virus envelope glycoprotein gp350 tricks the CR2? A molecular dynamics study.

The connection of Epstein Barr virus (EBV) with diseases such as Burkitt Lymphoma, Hodgkin disease, multiple sclerosis, systemic lupus erythematosus and various B-cell lymphomas made EBV glycoproteins one of the most popular vaccine immunogens. As a protein being encoded by EBV, the viral membrane envelope protein gp350 is studied extensively due to its abundancy on the surface and its interaction with complementary receptor, CR2. The binding of CR2 and gp350 not only leads to the entrance of the virus to the B-cells, but also prevents CR2 and C3d protein interactions that are required for immune response. Thus, understanding the inhibition of gp350 activity is crucial for vaccine development. Although, the active residues on gp350 structure were determined by several mutational studies, the exact mechanism of CR2 binding is still not clear. To this end, we have performed molecular docking followed by molecular dynamics simulations and MM-PBSA on wildtype and several mutated gp350 and CR2 structures. Apart from identifying crucial amino acids, the results of per-residue decomposition energy analysis clarified the individual energy contributions of amino acids and were also found to be accurate in differentiating the active site residues in CR2 binding. Here, we highlight the role of binding region residues (linker-1) but more interestingly, the dynamic relation between the distant sites of gp350 (linker-2 and D3 residues) and CR2. These findings can lead further vaccine development strategies by pointing to the importance of computationally found novel regions that can be potentially used to modulate gp350 activity.