Quinovosamycins: new tunicamycin-type antibiotics in which the α, β-1″,11′-linked N-acetylglucosamine residue is replaced by N-acetylquinovosamine

• Published in: Journal of antibiotics Vol. 69; no. 8; pp. 637 - 646
• Main Authors: Price, Neil PJ, Labeda, David P, Naumann, Todd A, Vermillion, Karl E, Bowman, Michael J, Berhow, Mark A, Metcalf, William W, Bischoff, Kenneth M
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 01-08-2016
• Subjects: 101/58; 631/45/221; 631/92/349; Acetylglucosamine - chemistry; Anti-Bacterial Agents - chemistry; Anti-Bacterial Agents - isolation & purification; Anti-Bacterial Agents - pharmacology; Bacteriology; Biomedical and Life Sciences; Bioorganic Chemistry; Enzyme Inhibitors - chemistry; Enzyme Inhibitors - isolation & purification; Enzyme Inhibitors - pharmacology; Glucosamine - analogs & derivatives; Glucosamine - chemistry; Life Sciences; Medicinal Chemistry; Microbiology; Organic Chemistry; original-article; Streptomyces - genetics; Streptomyces - metabolism; Tunicamycin - chemistry; Tunicamycin - isolation & purification; Tunicamycin - pharmacology
• ISSN: 0021-8820; 1881-1469
• DOI: 10.1038/ja.2016.49

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 (QVMs). QVMs are structurally akin to TUN, but uniquely in the 1″,11′-HexNAc sugar head group, 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.