RESUMO
Pactamycin, one of the most densely functionalized aminocyclitol antibiotics, has pronounced antibacterial, antitumor, antiviral, and antiplasmodial activities, but its development as a clinical drug was hampered by its broad cytotoxicity. Efforts to modulate the biological activity by structural modifications using synthetic organic chemistry have been difficult because of the complexity of its chemical structure. However, through extensive biosynthetic studies and genetic engineering, we were able to produce analogs of pactamycin that show potent antimalarial activity, but lack significant antibacterial activity, and are about 10-30 times less toxic than pactamycin toward mammalian cells. The results suggest that distinct ribosomal binding selectivity or new mechanism(s) of action may be involved in their plasmodial growth inhibition, which may lead to the discovery of new antimalarial drugs and identification of new molecular targets within malarial parasites.
Assuntos
Engenharia Genética/métodos , Malária/parasitologia , Pactamicina/biossíntese , Pactamicina/farmacologia , Plasmodium falciparum/efeitos dos fármacos , Streptomyces/genética , Streptomyces/metabolismo , Sequência de Aminoácidos , Antibacterianos/biossíntese , Antibacterianos/química , Antibacterianos/farmacologia , Antibacterianos/toxicidade , Antimaláricos/química , Antimaláricos/metabolismo , Antimaláricos/farmacologia , Antimaláricos/toxicidade , Técnicas de Inativação de Genes , Inativação Gênica , Células HCT116 , Humanos , Compostos de Metilureia/metabolismo , Pactamicina/análogos & derivados , Pactamicina/toxicidade , Streptomyces/enzimologia , Transferases/química , Transferases/deficiência , Transferases/genética , Transferases/metabolismoRESUMO
The lambda cI lysogenic transcript is unusual in having no leader. Expression of a cI-lacZ protein fusion was relatively resistant to kasugamycin and pactamycin, which inhibit translation initiation on transcripts with leaders. Our data imply that there are distinct differences in translation initiation between the two classes of transcripts.
