title: Antibacterial and toxicological evaluation of beta-lactams synthesized by immobilized beta-lactamase-free penicillin amidase produced by Alcaligenes sp.
abstract: Search for anti-beta-lactamase and synthesis of newer penicillin were suggested to overcome resistance to penicillin in chemotherapy. It was found that clavulanic acid, an ant-beta-lactamase was ineffective due to its structural modification by bacteria. Thus, there is a need for the synthesis of newer pencillins. Retro-synthesis was inspired by the success of forward reaction i.e.conversion of penicillin G to 6-aminopenicillanic acid (6-APA) by biological process. In the present study a better enzymatic method of synthesis of newer pencillin by a beta-lactamase-free penicillin amidase produced by Alcaligenes sp. is attempted. Antibacterial and toxicological evaluation of the enzymatically synthesized beta-lactams are reported. Condensation of 6-APA with acyl donor was found to be effective when the reaction is run in dimethyl formamide (DMF 50% v/v) in acetate buffer (25 mM pH 5.0) at 37 degrees C. Periplasm entrapped in calcium alginate exihibited the highest yield (approximately 34%) in synthesis. The minimum inhibitory concentration of the synthetic products against Staphylococcus aureus and Salmonella typhi varied between 20-80 microg/ml. Some of the products exhibited antibacterial activity against enteric pathogens. It was interesting to note that product A was potent like penicillin G. LD50 value of three products (product A, B and C) was more than 12 mg/kg. Furthermore, these synthetic beta-lactams did not exihibit any adverse effect on house keeping enzymes viz., serum glutamate oxalacetate-trans-aminase, serum glutamate pyruvate -trans-aminase, acid phosphatase, alkaline phosphatase of the test animals. The hematological profile (RBC and WBC) of the test animals also remained unaffected.
authors.affiliation: Department of Medicine, University of California at San Diego, California, USA.
authors.forename: Jiaur R
authors.initials: JR
authors.lastname: Gayen
authors.forename: Sutapa B
authors.initials: SB
authors.lastname: Majee
authors.forename: Shuvendu
authors.initials: S
authors.lastname: Das
authors.forename: Timir B
authors.initials: TB
authors.lastname: Samanta
mesh_terms: D000421:Alcaligenes / Q000187:drug effects / Q000201:enzymology*; D000818:Animals; D000900:Anti-Bacterial Agents / Q000096:biosynthesis* / Q000633:toxicity; D018914:Cells, Immobilized / Q000201:enzymology / Q000378:metabolism; D007928:Lethal Dose 50; D008826:Microbial Sensitivity Tests; D010399:Penicillin Amidase / Q000378:metabolism* / Q000633:toxicity; D013211:Staphylococcus aureus / Q000187:drug effects; D047090:beta-Lactams / Q000378:metabolism* / Q000633:toxicity
chemical_list: D000900:Anti-Bacterial Agents; D047090:beta-Lactams; D010399:Penicillin Amidase