Bioactive Polycyclic Tetramate Macrolactams from Lysobacter enzymogenes and Their Absolute Configurations by Theoretical ECD Calculations

Abstract

Two new polycyclic tetramate macrolactams, lysobacteramides A (1) and B (2), together with HSAF (heat-stable antifungal factor, 3), 3-dehydroxy HSAF (4), and alteramide A (5) were isolated from a culture of Lysobacter enzymogenes C3 in nutrient yeast glycerol medium. Their structures were determined by MS and extensive NMR analysis. The absolute configurations of 1-5 were assigned by theoretical calculations of their ECD spectra. Although HSAF and analogues were reported from several microorganisms, their absolute configurations had not been established. The isolation and the absolute configurations of these compounds revealed new insights into the biosynthetic mechanism for formation of the polycycles. Compounds 1-4 exhibited cytotoxic activity against human carcinoma A549, HepG2, and MCF-7 cells with IC50 values ranging from 0.26 to 10.3 μM. Compounds 2 and 3 showed antifungal activity against Fusarium verticillioides with IC50 value of 47.9 and 6.90 μg/mL, respectively.

Activation and characterization of a cryptic gene cluster reveals a cyclization cascade for polycyclic tetramate macrolactams

“…Given that 11 and 4 exhibited almost identical ECD spectra (Fig. S8†), 4 the absolute configuration of 11 was deduced as 5 R , 6 S , 8 S , 10 S , 11 R , 12 R , 13 S , 16 R and 23 S . Similarly, the structures of pactamides B–F ( 12–16 ) were determined (see the ESI† for the structure elucidation).…”

“…1). 4 The relative configuration of 11 was deduced by the proton coupling constants ( Z Δ 2,3 J 2,3 11.5 Hz; E Δ 17,18 J 17,18 15.0 Hz, Table S4†) and NOESY correlations (Fig. S7†).…”

“…S7†). On the basis of the biosynthetic origin of the l -ornithine of PTMs, 1,4 the S -configuration was assignable to C-23. Given that 11 and 4 exhibited almost identical ECD spectra (Fig.…”

“…1), 1 such as the 5/5 ring system in alteramides ( 1 , 2 ), 2 5/5/6 ring system in HSAF (heat-stable antifungal factor, 3 ), lysobacteramide B ( 4 ), 3,4 and frontalamides ( 5 , 6 ), 5 5/6/5 ring system in ikarugamycin ( 7 ) 6 and butremycin ( 8 ), 7 and 5/4/6 ring system in 9 . 8 PTMs exhibit a wide range of antifungal, antibacterial, antiprotozoal, antiulcer, antiviral, cytotoxic, and apoptosis-inducing biological activities.…”

Structural diversity of anti-pancreatic cancer capsimycins identified in mangrove-derived Streptomyces xiamenensis 318 and post-modification via a novel cytochrome P450 monooxygenase

“…Based on their unique biosynthetic origins, PTMs have multiple biological activities that involve antiprotozoal1415, antifungal71516, antibacterial91718 and antiviral actions19. They also inhibit cholesteryl ester accumulation in J774 macrophages14.…”