Cunninghamella blakesleeana-mediated biotransformation of a contraceptive drug, desogestrel, and anti-MDR-Staphylococcus aureus activity of its metabolites

Abstract

Staphylococcus aureus is one of the most infectious agents among staphylococcal bacteria. Currently many strains of S. aureus have developed resistance against available antibiotics. Therefore, the treatment of infections caused by them is a major challenge. During current study, desogestrel (1), a contraceptive drug, was found to be a potent growth inhibitor of drug resistant strains of S. aureus. Therefore, in search of new and effective agents against multi-drug resistant S. aureus strains, whole-cell bio-catalytic conversion of desogestrel (1) by Cunninghamella blakesleeana ATCC 8688A at pH 7.0 and 25 °C was carried out, yielding three new metabolites, 13-ethyl-11-methylene-18,19-dinor-17α-pregn-4-en-20-yn-6β,15β,17β-triol (2), 13-ethyl-11-methylene-18,19-dinor-17α-pregn-4-en-20-yn-3β,6β,17β-triol (3), and 13-ethyl-11-methylene-18,19-dinor-17α-pregn-20-yn-3α,5α,6β,17β-tetraol (4), along with a known metabolite, 13-ethyl-11-methylene-18,19-dinor-17α-pregn-4-en-20-yn-6β,17β-dihydroxy-3-one (5). Among them, compounds 1-2 showed a potent activity against S. aureus EMRSA-17, S. aureus NCTC 13277 (MRSA-252), and S. aureus NCTC 13143, and clinically isolated Pakistani strain of S. aureus in an in vitro Microplate Alamar Blue Assay (MABA). Vancomycin was used as the standard drug in this assay. In addition, compound 1 also showed a significant activity against vancomycin-resistant S. aureus (VRSA) ATCC 700699. Compounds 1-5 were also evaluated against 3T3 normal cell line (mouse fibroblast) where they all were identified as non-cytotoxic. The present study thus provides new leads for the development of anti-bacterial drugs against MDR S. aureus.

Seven new metabolites of drostanolone heptanoate by using Beauveria bassiana, and Macrophomina phaseolina cell suspension cultures

“…An OH group at C-5 (d 77.0) was placed as a, based on the comparison of the reported chemical shis for 5a-OH in steroids. 15,20 Thus the structure of a new metabolite was identied as 2a-methyl-3b,5a,17b-trihydroxyandrostane (7).…”

“…12 Similarly, several metabolites of drostanolone on incubation with cryopreserved human hepatocytes are also reported. 13 In continuation of our structural transformation studies on steroidal drugs, [14][15][16][17][18][19][20] biotransformation of drostanolone heptanoate (1) was carried out. Based on small scale screening results, compound 1 was subjected to biotransformation by using two microbial cell cultures, Beauveria bassiana, and Macrophomina phaseolina, for the rst time, yielding seven new, and two known compounds.…”

Biotransformation of Steroids Using Different Microorganisms

“…Fusarium oxysporum biotransformed to 126 in a mixture of four hydroxylated derivatives (127-129 and 130), which were characterized as their acetylated derivatives; the hydroxylation was favorably in C-7 stereospecifically (α orientation) in the 3β-hydroxy-Δ 5 -steroids, while Colletotrichum musae biotransformed to 126-127 by reducing the carbonyl group in C-17 ( Figure 16) [56]. In the biotransformation of 126 using Penicillium griseopurpureum and P. glabrum, the following was produced; hydroxylated derivatives in C-7α (95), C-14α (94) and C-15α (117), with 11 being the main product. In addition, P. griseopurpureum generated products for the Baeyer Villiger oxidation to give the lactone D ring (testolactone, 13) and its hydroxylated derivative at C-15α (15α-hydroxy-17α-oxa-d-homo-androst-4-en-3,17-dione, 135); while P. glabrum generated the compounds, 3β-hydroxy-17α-oxa-D-homo-androst-5-en-17-one (136) and 3β-hydroxy-17α-oxa-D-homo-5α-androstan-17-one (137) (Figure 16) [82].…”

“…The ethynodiol diacetate (192) is a synthetic derivative 1, used as an oral contraceptive because it inhibits the ovulation process. The microbiological transformation of 192 using Cunninghamella elegans produced four hydroxylated compounds (Figure 26) [94].…”

<i>Fusarium lini</i> Potential for the Biotransformation of Norandrostenedione and Evaluation of Urease and Chymotrypsin Properties of the Transformed Products

“…Biocatalysts can be used for regio-and stereo-selective reactions, or to introduce chirality in a way that would be very difficult, if not impossible, with classical chemical syntheses [4]. A number of studies have shown that several androgenic steroids have been biotransformed by fungi into metabolites with numerous biological properties [5] [6] [7]. Because of their stereochemistry (presence of many asymmetric centres and inert hydrocarbon skeletons), the hydroxylation, oxidation and epoxidation of steroids are difficult tasks for organic chemists.…”