Novel Penicillins Synthesized by Biotransformation Using Laccase from Trametes spec.

Abstract

There is an urgent need to develop new antimicrobial agents due to increasing bacterial resistance to therapeutically used drugs. Most methicillin-resistent Staphylococcus aureus (MRSA) strains are resistent not only to b-lactams, but also to most other antimicrobial agents.1) Penicillin resistance among Streptococcus pneumoniae strains is widely accepted as a global problem. [2][3][4][5] Bacteria have developed several strategies for escaping the lethal action of b-lactams. It may be expected that specific circumstance will make one the more effective stragegy than the other. 6) Much effort has been devoted to the discovery of drugs which would not be cleaved by b-lactamases of pathogenic strains and which have suitable physicochemical and pharmacodynamic profiles. 7,8) The modifications of b-lactam antibiotics could not keep pace with the development of resistance in the pathogenic microorganisms, so that numerous bacteria, among them multidrug resistant Staphylococcus strains, can no longer be treated with the currently available b-lactam antibiotics. 1,9,10) Besides the modification of existing antibiotics by chemical or biochemical methods the coupling of presently used antibiotics with other bioactive compounds or components from them which are not in use till now is a promising way to generate novel molecules with improved therapeutic properties.Laccase (benzenediol:oxygen oxidoreductase, EC 1.10.3.2), classically considered a hydroquinone oxidizing enzyme, is able to oligomerize molecules. Up to now main application fields of this enzyme are waste detoxification, textile dye transformation, biosensors and diagnostic application, where the capability to catalyze polymerization reactions is used. 11-13)Recently we reported about our synthetic results on coupling reactions with laccase.14-17) Now we have employed laccase to achieve derivatisation of b-lactam antibiotics and to couple them with derivatives of 2,5-dihydroxybenzoic acid. These derivatives are structurally related to the ganomycins, a new chemical class of antibacterial compounds 18) and to other antibacterial active isolates 19,20) therefore interesting as coupling partner for b-lactams using laccase as initiator of the reaction to produce novel hybridantibiotics by biotransformation.The use of laccase for the derivatisation of antibiotics is limited to a few examples including the phenolic oxidation of 7-(4-hydroxyphenylacetamido)cephalosporinic acid, 21) the dimerization of penicillin X 22) and the oxidative coupling of hydroquinone and mithramicine. 23) In the examples realized to date, the sought object of enhancement of the bioactive effect has not been achieved. 21-23)The aim of this study was (i) to investigate whether laccase can be used for the synthesis of novel penicillins by heteromolecular coupling of two different compounds, (ii) to characterize the products of the reaction, and (iii) to analyze the biological activity of the novel penicillins. Results and DiscussionBiotransformation of Amoxicillin and Ampicillin by Laccase of Tr...

Improvement of the Antifungal Activity Against Botrytis Cinerea of Syringic Acid, a Phenolic Acid From Grape Pomace

“…For instance, the ferulic acid was modified using laccase to produce two dimeric molecules with higher antioxidant capacity than the ferulic acid 16 . An additional example is the enzymatic modification of antibiotics using nitrogen compounds, the products showed higher antibiotic activity than the initial antibiotic 20,21 . Similarly, in this study, the enzymatic modification of syringic acid with aniline increased its antifungal activity.…”

“…Another example is the coupling between p-hydroquinones with p-aminobenzoic acid 18 . On the other hand, modification of antibiotics using laccase coupling reactions produced compounds with lower activities 19 , however, using nitrogen compounds to modify the antibiotics, the synthesized products showed higher antibacterial activities 20,21 . The anticancer activity of naphtohydroquinones has been improved by nuclear monoamination with anilines using laccase 22 .…”

Laçasse Catalyzed-Synthesis of 4,4'-Biphenyldiamine From P-Chloroaniline. Evaluation of Antifungal and Antioxidant Activities

“…Another example is the coupling between p-hydroquinones with p-aminobenzoic acid 8 . Antibiotic modifications using laccase coupling reactions have shown products with lower activities 9 ; however, using nitrogen compounds to modify the antibiotics, the synthesized products showed higher antibacterial activities 10,11 . The anticancer activity of naphtohydroquinones has been improved by nuclear monoamination with anilines using laccase 12 .…”

Laccase Functionalization of Flax and Coconut Fibers

“…This family of enzymes has found numerous applications in diverse fields like environmental pollution control [1], organic synthesis [2,3] and several industrial areas like pharmaceutical [4,5], food [6,7], textile [8,9], etc.…”