RESUMO
The increase in multi-drug resistant pathogenic bacteria is making our current arsenal of clinically used antibiotics obsolete, highlighting the urgent need for new lead compounds with distinct target binding sites to avoid cross-resistance. Here we report that the aromatic polyketide antibiotic tetracenomycin (TcmX) is a potent inhibitor of protein synthesis, and does not induce DNA damage as previously thought. Despite the structural similarity to the well-known translation inhibitor tetracycline, we show that TcmX does not interact with the small ribosomal subunit, but rather binds to the large subunit, within the polypeptide exit tunnel. This previously unappreciated binding site is located adjacent to the macrolide-binding site, where TcmX stacks on the noncanonical basepair formed by U1782 and U2586 of the 23S ribosomal RNA. Although the binding site is distinct from the macrolide antibiotics, our results indicate that like macrolides, TcmX allows translation of short oligopeptides before further translation is blocked.
Assuntos
Amycolatopsis/efeitos dos fármacos , Regulação Bacteriana da Expressão Gênica/efeitos dos fármacos , Amycolatopsis/genética , Amycolatopsis/metabolismo , Sítios de Ligação , Microscopia Crioeletrônica , Farmacorresistência Bacteriana , Escherichia coli , Células HEK293 , Humanos , Testes de Sensibilidade Microbiana , Modelos Moleculares , Mutação , Naftacenos/química , Naftacenos/farmacologia , Ligação Proteica , Biossíntese de Proteínas/efeitos dos fármacos , Conformação Proteica , Ribossomos/metabolismoRESUMO
One new carbamothioic S-acid derivative (1) and five known kigamicin derivatives (2-6) were isolated from the fermentation extract of Amycolatopsis alba DSM 44262Δabm9 elicited by N-acetyl-D-glucosamine. HPLC-DAD-UV analyses indicated that the DSM 44262Δabm9 strain did not produce these metabolites originally and the production of 1-6 was induced by adding 25 mM N-acetyl-D-glucosamine in the culture medium. The structures of 1-6 were identified on the basis of NMR spectroscopic data and high-resolution ESIMS. These results highlight that addition of N-acetyl-D-glucosamine in the microbial culture medium could activate cryptic gene expression, induce and increase the production of new or known secondary metabolites.