Streptomyces coelicolor strains lacking polyprenol phosphate mannose synthase and protein O-mannosyl transferase are hyper-susceptible to multiple antibiotics.
Streptomyces coelicolor strains lacking polyprenol phosphate mannose synthase and protein O-mannosyl transferase are hyper-susceptible to multiple antibiotics.
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DOI：
10.1099/mic.0.000605
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发表时间：
2018-03
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;Read N;Varghese A;Kershaw C;Hancock Y;Smith MCM
聚戊烯醇磷酸甘露糖（PPM）是细菌细胞质外糖基转移酶使用的脂连接糖供体。PPM由聚戊烯醇磷酸甘露糖合成酶Ppm 1合成，在大多数放线菌中，PPM在蛋白质糖基化中用作蛋白质O-甘露糖基转移酶Pmt的糖供体。Ppm 1和Pmt在酵母和人类中具有同源物，它们是蛋白质O-甘露糖基化所必需的。放线菌也使用PPM进行脂聚糖的生物合成。在这里，我们表明天蓝色链霉菌的ppm 1突变体对靶向细胞壁生物合成的一些抗生素的敏感性增加。pmt突变体还具有轻度增加的抗生素敏感性，特别是对β-内酰胺类和万古霉素。尽管正常诱导万古霉素基因簇vanSRJKHAX，pmt和ppm 1突变体仍然对万古霉素高度敏感，表明耐药机制在转录后被阻断。差异RNA表达分析表明，分解代谢途径下调和合成代谢的上调ppm 1突变体相比，父母或补充菌株。值得注意的是在ppm 1突变体中脂肪酸生物合成基因的表达增加。使用拉曼光谱法证实了脂质组成的变化，这表明ppm 1-突变体与亲本或互补突变体相比具有更大的不饱和脂肪酸的相对比例。综上所述，这些数据表明，不能合成PPM（ppm 1）和糖蛋白组（pmt-突变体）的损失可能会破坏性地影响膜或细胞包膜功能，导致内在的损失，并在万古霉素的情况下，获得性抗生素耐药性。
Polyprenol phosphate mannose (PPM) is a lipid-linked sugar donor used by extra-cytoplasmic glycosyl tranferases in bacteria. PPM is synthesiszed by polyprenol phosphate mannose synthase, Ppm1, and in most Actinobacteria is used as the sugar donor for protein O-mannosyl transferase, Pmt, in protein glycosylation. Ppm1 and Pmt have homologues in yeasts and humans, where they are required for protein O-mannosylation. Actinobacteria also use PPM for lipoglycan biosynthesis. Here we show that ppm1 mutants of Streptomyces coelicolor have increased susceptibility to a number of antibiotics that target cell wall biosynthesis. The pmt mutants also have mildly increased antibiotic susceptibilities, in particular to β-lactams and vancomycin. Despite normal induction of the vancomycin gene cluster, vanSRJKHAX, the pmt and ppm1 mutants remained highly vancomycin sensitive indicating that the mechanism of resistance is blocked post-transcriptionally. Differential RNA expression analysis indicated that catabolic pathways were downregulated and anabolic ones upregulated in the ppm1 mutant compared to the parent or complemented strains. Of note was the increase in expression of fatty acid biosynthetic genes in the ppm1- mutant. A change in lipid composition was confirmed using Raman spectroscopy, which showed that the ppm1- mutant had a greater relative proportion of unsaturated fatty acids compared to the parent or the complemented mutant. Taken together, these data suggest that an inability to synthesize PPM (ppm1) and loss of the glycoproteome (pmt- mutant) can detrimentally affect membrane or cell envelope functions leading to loss of intrinsic and, in the case of vancomycin, acquired antibiotic resistance.
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