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

Atia -Tul-Wahab (1) , Mahwish Siddiqui (1) , Iman Ibrahim (2, 3) , Arifa Hussain (1) , El Hassan Ajandouz (2) , Akram Hijazi (3) , Elias Baydoun (4) , M. Iqbal Choudhary (1, 5)

1 University of Karachi
2 ISM2 - Institut des Sciences Moléculaires de Marseille
3 LU / ULB - الجامعة اللبنانية [بيروت] = Lebanese University [Beirut] = Université libanaise [Beyrouth]
4 AUB - American University of Beirut [Beyrouth]
5 King Abdulaziz University

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.

Mots clés: Drug resistant Staphylococcus aureus; Desogestrel; Biotransformation; Cunninghamella blakesleeana; 15b-Dihydroxy-desogestrel; Anti-bacterial; Cytotoxicity

Domaines: Chimie thérapeutique; Pharmacologie

Atia -Tul-Wahab, Mahwish Siddiqui, Iman Ibrahim, Arifa Hussain, El Hassan Ajandouz, et al.. Cunninghamella blakesleeana -mediated biotransformation of a contraceptive drug, desogestrel, and anti-MDR- Staphylococcus aureus activity of its metabolites. Bioorganic Chemistry, 2018, 77, pp.152-158. ⟨10.1016/j.bioorg.2017.12.027⟩. ⟨hal-01793446⟩