Naslov
Virtual screening and experimental verification to identify potential inhibitors of the ErmC methyltransferase responsible for bacterial resistance against macrolide antibiotics.

Autori
Feder, Marcin ; Purta, Elzbieta ; Maravić Gordana ; Bujnicki, Janusz

Vrsta, podvrsta i kategorija rada
Sažeci sa skupova, sažetak, znanstveni

Izvornik
Book of abstracts / - , 2007

Skup
15th Annual International Conference on Intelligent Systems for Molecular Biology (ISMB) & 6th European Conference on Computational Biology (ECCB)

Mjesto i datum
Beč, Austrija, 21.07.2007. - 25.07.2007

Vrsta sudjelovanja
Poster

Vrsta recenzije
Međunarodna recenzija

Ključne riječi
antibiotic resistance; Erm methlytransferases; inhibitors

Sažetak
Methyltransferases from the Erm family catalyze SadenosylLmethioninedependent modification of a specific adenine residue in bacterial 23S rRNA, thereby conferring resistance to clinically important macrolide, lincosamide and streptogramin B antibiotics. Thus far, no inhibitors of these enzymes have been identified or designed that would effectively abolish the resistance in vivo. We used the crystal structure of ErmC' methyltransferase as a target for structurebased virtual screening of a database comprising 58679 leadlike compounds. Among 77 compounds selected for experimental validation (63 predicted to bind to the catalytic pocket and 14 compounds predicted to bind to the putative RNAbinding site) we found several novel inhibitors, which reduce the minimal inhibitory concentration of a macrolide antibiotic erythromycin for Escherichia coli with constitutively expressed ErmC' gene. Four of them have IC50 values in the micromolar range and can be regarded as new lead structures with the potential for further optimization, aiming at the development of clinically useful inhibitors.

Izvorni jezik
Engleski

Znanstvena područja
Biologija

POVEZANOST RADA