Disruption of the GDP-mannose synthesis pathway in Streptomyces coelicolor results in antibiotic hyper-susceptible phenotypes.
Disruption of the GDP-mannose synthesis pathway in Streptomyces coelicolor results in antibiotic hyper-susceptible phenotypes.
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DOI：
10.1099/mic.0.000636
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发表时间：
2018-04
期刊：
影响因子：
--
通讯作者：
Smith MCM
中科院分区：
文献类型：
--
作者：
Howlett R;Anttonen K;Read N;Smith MCM
放线菌细菌使用聚戊烯醇磷酸甘露糖作为细胞质外糖基转移酶的脂质连接的糖供体，所述细胞质外糖基转移酶将甘露糖转移至细胞包膜聚合物，包括糖蛋白和糖脂。我们最近发现，天蓝色链霉菌编码聚戊烯醇磷酸甘露糖合酶的基因ppm 1突变的菌株既对噬菌体φC31有抗性，又大大增加了对主要作用于细胞壁生物合成的抗生素的敏感性。在这里，我们表明，突变的基因编码的酶，在磷酸聚戊烯醇甘露糖合成途径中的Ppm 1上游的行为也可以赋予噬菌体耐药性和抗生素超敏感性。GDP-甘露糖是Ppm 1的底物，由GDP-甘露糖焦磷酸化酶（GMP; ManC）合成，该酶使用GTP和甘露糖-1-磷酸作为底物。磷酸甘露变位酶（PMM; ManB）将甘露糖-6-磷酸转化为甘露糖-1-磷酸。S.具有GMP活性敲低或具有编码PMM的sco 3028中的突变的天蓝色菌株获得类似于ppm 1-突变体的表型，即φC31对抗生素的抗性和敏感性。然而，观察到菌株表型的差异。虽然ppm 1-菌株具有小菌落表型，但sco 3028：：Tn 5062突变体具有极小的菌落表型，表明甚至更大的生长缺陷。 此外，我们不能产生其中由sco 3039和sco 4238编码的GMP活性被完全敲除的菌株，表明GMP也是生长的重要酶。可能GDP-甘露糖处于提供替代核苷酸糖供体的代谢分支点。
Actinomycete bacteria use polyprenol phosphate mannose as a lipid linked sugar donor for extra-cytoplasmic glycosyl transferases that transfer mannose to cell envelope polymers, including glycoproteins and glycolipids. We showed recently that strains of Streptomyces coelicolor with mutations in the gene ppm1 encoding polyprenol phosphate mannose synthase were both resistant to phage φC31 and have greatly increased susceptibility to antibiotics that mostly act on cell wall biogenesis. Here we show that mutations in the genes encoding enzymes that act upstream of Ppm1 in the polyprenol phosphate mannose synthesis pathway can also confer phage resistance and antibiotic hyper-susceptibility. GDP-mannose is a substrate for Ppm1 and is synthesised by GDP-mannose pyrophosphorylase (GMP; ManC) which uses GTP and mannose-1-phosphate as substrates. Phosphomannomutase (PMM; ManB) converts mannose-6-phosphate to mannose-1-phosphate. S. coelicolor strains with knocked down GMP activity or with a mutation in sco3028 encoding PMM acquire phenotypes that resemble those of the ppm1- mutants i.e. φC31 resistant and susceptible to antibiotics. Differences in the phenotypes of the strains were observed, however. While the ppm1- strains have a small colony phenotype, the sco3028 :: Tn5062 mutants had an extremely small colony phenotype indicative of an even greater growth defect. Moreover we were unable to generate a strain in which GMP activity encoded by sco3039 and sco4238 is completely knocked out, indicating that GMP is also an important enzyme for growth. Possibly GDP-mannose is at a metabolic branch point that supplies alternative nucleotide sugar donors.
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