期刊
ANTIMICROBIAL AGENTS AND CHEMOTHERAPY
卷 62, 期 7, 页码 -出版社
AMER SOC MICROBIOLOGY
DOI: 10.1128/AAC.00193-18
关键词
biosynthesis; antibiotic; nucleoside; translocase I; resistance; MraY inhibitor
资金
- National Institutes of Health [AI087849]
- National Center for Advancing Translational Sciences [UL1TR000117]
- Fonds der Chemischen Industrie (Germany) (Sachkostenzuschuss)
- German federal state of Lower Saxony (Lichtenberg doctoral fellowship [CaSuS program])
- NATIONAL CENTER FOR ADVANCING TRANSLATIONAL SCIENCES [UL1TR001998, UL1TR000117] Funding Source: NIH RePORTER
- NATIONAL INSTITUTE OF ALLERGY AND INFECTIOUS DISEASES [R01AI087849] Funding Source: NIH RePORTER
Muraymycins are antibacterial natural products from Streptomyces spp. that inhibit translocase I (MraY), which is involved in cell wall biosynthesis. Structurally, muraymycins consist of a 5'-C-glycyluridine (GlyU) appended to a 5 ''-amino-5 '' deoxyribose (ADR), forming a disaccharide core that is found in several peptidyl nucleoside inhibitors of MraY. For muraymycins, the GIyU-ADR disaccharide is further modified with an aminopropyl-linked peptide to generate the simplest structures, annotated as the muraymycin D series. Two enzymes encoded in the muraymycin biosynthetic gene cluster, Mur29 and Mur28, were functionally assigned in vitro as a MOTP-dependent nucleotidyltransferase and a MOTP-dependent phosphotransferase, respectively, both modifying the 3 ''-OH of the disaccharide. Biochemical characterization revealed that both enzymes can utilize several nucleotide donors as cosubstrates and the acceptor substrate muraymycin also behaves as an inhibitor. Single-substrate kinetic analyses revealed that Mur28 preferentially phosphorylates a synthetic GlyU-ADR disaccharide, a hypothetical biosynthetic precursor of muraymycins, while Mur29 preferentially adenylates the D series of muraymycins. The adenylated or phosphorylated products have significantly reduced (170-fold and 51-fold, respectively) MraY inhibitory activities and reduced antibacterial activities, compared with the respective unmodified muraymycins. The results are consistent with Mur29catalyzed adenylation and Mur28-catalyzed phosphorylation serving as complementary self-resistance mechanisms, with a distinct temporal order during muraymycin biosynthesis.
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