Biosynthetic Studies and Genetic Engineering of Pactamycin Analogs with Improved Selectivity toward Malarial Parasites

SummaryPactamycin, 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.

Graphical AbstractFigure optionsDownload full-size imageDownload high-quality image (446 K)Download as PowerPoint slideHighlights► PtmB, PtmD, PtmH, PtmL, and PtmM play critical roles in pactamycin biosynthesis ► Genetically engineered S. pactum produce pactamycin analogs with promising biological activity ► The new analogs, TM-025 and TM-026, have pronounced antimalarial activity ► TM-025 and TM-026 are 10–30-fold less toxic than pactamycin for mammalian cells