Quinovosamycins: New tunicamycin-type antibiotics in which the alpha, beta-1", 11'-linked N-acetylglucosamine residue is replaced by N-acetylquinovosamine.

Authors: Price, Neil; Labeda, David; Naumann, Todd; Vermillion, Karl; Bowman, Michael; Berhow, Mark; METCALF, WILLIAM - University Of Illinois; Bischoff, Kenneth

Submitted to: Journal of Antibiotics
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 1/11/2016
Publication Date: 5/18/2016
Citation: Price, N.P.J., Labeda, D.P., Naumann, T.A., Vermillion, K.E., Bowman, M.J., Berhow, M.A., Metcalf, W.W., Bischoff, K.M. 2016. Quinovosamycins: New tunicamycin-type antibiotics in which the alpha, beta-1", 11'-linked N-acetylglucosamine residue is replaced by N-acetylquinovosamine. Journal of Antibiotics. 69(8):637-646. doi: 10.1038/ja.2016.49.

Interpretive Summary: Several Streptomyces soil bacteria make natural products called tunicamycins that have potent antimicrobial activity. Using a bioinformatic database search based on two of the known tun genes (tunB and tunD), we identified four new tunicamycin-producing organisms. Chemical analysis of the fermentation broth from these new strains showed that one of them, Streptomyces niger NRRL B-3857, which is housed in the ARS Culture Collection in Peoria, IL, produces very unique new tunicamycins, that we have named quinovosamycins. The quinovosamycins are structurally similar to the tunicamycins, but the sugar headgroup is different: GlcNAc for the known tunicamycins, but QuiNAc for the new quinovosamycins. This finding has unexpected consequences for the way that tunicamycins and quinovosamycins are biosynthesized. The relative antimicrobial potency of the quinovosamycins and tunicamycins was measured, and the quinovosamycins were found to have unexpected high activity against yeast and certain bacteria (Bacillus subtilis). The availability of these new compounds (quinovosamycins) will allow comparative testing with the aim of developing new, and possibly selective antimicrobial agents.

Technical Abstract: Tunicamycins (TUN) are potent inhibitors of polyprenyl phosphate N-acetylhexosamine 1-phosphate transferases (PPHP), including essential eukaryotic GPT enzymes and bacterial HexNAc 1-P translocases. Hence, TUN blocks the formation of eukaryotic N-glycoproteins and the assembly of bacterial call wall polysaccharides. The genetic requirement for TUN production is well established. Using two genes unique to the TUN pathway (tunB and tunD) as probes we identified four new prospective TUN-producing strains. Chemical analysis showed that one strain, Streptomyces niger NRRL B-3857, produces TUN plus new compounds, named quinovosamycins (QVM). QVM are structural akin to TUN, but uniquely differ in the 1'',11'-HexNAc sugar headgroup, which is invariably D-GlcNAc for the known TUN, but is D-QuiNAc for the QVM. Surprisingly, this modification has only a minor effect on either the inhibitory or antimicrobial properties of QVM and TUN. These findings have unexpected consequences for TUN/QVM biosynthesis, and for the specificity of the PPHP enzyme family.