Generation of methylated violapyrones with improved anti-influenza A virus activity by heterologous expression of a type III PKS gene in a marine Streptomyces strain.

Heterologous expression of the type III polyketide synthase (PKS) gene vioA in marine-derived Streptomyces youssoufiensis OUC6819 led to production of six violapyrones (VLPs), including four novel compounds VLPs Q–T ( 1 – 4 ) and two known compounds VLPs B and I ( 5 and 6) . The structures of 1 – 4 were elucidated by a combination of spectroscopic analyses, including HR-ESIMS and 1D and 2D NMR data, demonstrating that 1 – 4 are novel VLPs which are methylated at 4-OH with their corresponding non-methylated counterparts to be VLP A, 5 and 6 and VLP C, respectively. Anti-influenza A [H1N1 (A/Virginia/ATCC1/2009) and H3N2 (A/Aichi/2/1968)] virus activity of compounds 1 – 6 as well as VLPs A and C were then evaluated using ribavirin as a positive control (IC 50  = 66.7 and 99.6 μM). The results revealed that these VLPs showed considerable anti-H1N1 and anti-H3N2 activities with IC 50 values of 30.6–132.4 μM and 45.3–150.0 μM, respectively. Notably, all the methylated VLPs displayed better anti-virus activity than their non-methylated counterparts, among which compound 3 (VLP S) exhibited the best activities. Interestingly, methylation at 4-OH has negative effect on the anti-MRSA (methicillin-resistant Staphylococcus aureus ) activity instead, with methylated VLPs displaying decreased ( 2 ) or abolished ( 3 and 4 ) activities in comparison with each of their non-methylated counterparts. [ABSTRACT FROM AUTHOR]