1. Shahid chamran Univercity of Ahwaz 2. Shahid chamran Univercity of Ahwaz
Drug resistant infectious of pseudomonas aeruginosa bacteria comprise serious issues against human health. the bacteria play important role primarily in hospital acquired infections of bloodstream and urinary with consequent pneumonia. nowadays p. aeruginosa become a multi drug resistant infection with about 10-20 percent of frequency among life threatening infectious. the enzyme of verona integron-encoded of metallo -beta- lactamase or briefly, vim-11, by hydrolyzing antibiotics of beta lactams renders them ineffective against this infectious. beta lactams are the major antibiotics used for such cases. the possibility of beta lactamase encoding plasmid transfer to other bacteria as, enterobacter spp. leads to pathogen resistance to beta lactam antibiotics. the metalloenzyme of vim-11, ec 126.96.36.199 with two metal ions of zn in its active site with molecular weight of 26 kd and optimum ph of 7.5 has no crystal structure in pdb bank (www.rcsb.org) for drug design and docking experiments.
The sequence of vim-11 enzyme with accession:aat36613.1 was retrieved from ncbi website (www.ncbi.nlm.nih.gov/protein) in fasta format. the modeling and energy minimization experiment were performed on swiss-model server (https://swismodelexpacy.org) and gromacs software respectively. from sixteen models extracted here the best one was selected based on rampage analysis and used for further experiments. this structure then equilibrated at ph7 and 1 atmosphere of pressure by performing a short simulation of 10ns of duration. the structure then refined for blind docking experiments in hex (version 8.0.0). the docking experiments were done using different available antibiotic to study their interactions and to survey their bind sites. coordinate structures of antibiotics of amikacin , aztreonam, ceftazidime, ciprofloxacin, cephalosporin, gentamicin, imipenem, meropenem, penicillin, tazobactam, ticarcillin and tobramycin were obtained from pubchem website (www.pubchem.ncbi.nlm.nih.gov) in sdf format and converted pdb format by openbable software and optimized in hyperchem8 software. docking results were analyzed in raswin, weblab viewer and excell software.
Our docking results show that based on binding sites of candidate drugs and their distance to enzyme active site and zink ions, penicillin, ceftazidime, aztreonam, cephalosporin and ciprofloxacin among tested drugs bind in near vicinity to enzyme active site and by the way we hypothesize that they could compete with enzyme natural substrate and deactive the enzyme and help to overcome drug resistance of the bacteria.
binding energy and binding orientation of these five antibiotics indicate that ceftazidime express more binding potency with suitable orientation that resiste against hydrolysis of its beta- lactam ring by vim-11 enzyme.
Based on our findings we expect that ceftazidime could be used as the base antibiotic for p.aeruginosa interaction in multi drug treatment.