An operon encoding enzymes for synthesis of a putative extracellular carbohydrate attenuates acquired vancomycin resistance in Streptomyces coelicolor.
An operon encoding enzymes for synthesis of a putative extracellular carbohydrate attenuates acquired vancomycin resistance in Streptomyces coelicolor.
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DOI：
10.1099/mic.0.000763
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发表时间：
2019-01
期刊：
影响因子：
1.5
通讯作者：
N. Read;R. Howlett;Margaret C. M. Smith
中科院分区：
文献类型：
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作者：
N. Read;R. Howlett;Margaret C. M. Smith
放线菌细菌使用聚戊醇磷酸甘露糖作为脂联糖供体，用于细胞质外糖基转移酶，将甘露糖转移到细胞包膜聚合物，包括糖蛋白和糖脂。编码聚prenol磷酸甘露糖合成酶的基因ppm1和编码o -甘露糖基转移酶的基因pmt突变的链霉菌菌株对噬菌体<s:2> c31具有耐药性，并且对包括万古霉素在内的一些抗生素的敏感性大大增加。本研究分离了万古霉素敏感性的第二位点抑制因子。抑制菌株分为两组。1组菌株对万古霉素、替柯planin和β-内酰胺的耐药性增加，且vanSR编码的双组分传感器调控系统发生突变，导致vanSRJKHAX簇的扩增。第2组菌株仅增加了对万古霉素的耐药性，这些菌株大多在sco2592或sco2593中发生突变，这些基因在磷酸盐存在下被抑制，可能是合成含磷酸盐的细胞外聚合物所必需的。在一些抑制菌株中，抗性仅在磷酸盐含量有限的培养基中（模仿野生型S. coelicolor的表型）观察到增强，但两株菌株DT3017_R21 （ppm1- vanr -）和DT3017_R15 （ppm1- sco2593-）在高磷酸盐含量的培养基中仍保持抗性。这些结果支持了这样一种观点，即金黄色葡萄球菌对万古霉素的耐药性是在赋予耐药性的机制和至少一种干扰通过sco2594-sco2593-sco2592操纵子介导的耐药性机制之间的权衡。
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. Strains of Streptomyces coelicolor with mutations in the gene ppm1, encoding polyprenol phosphate mannose synthase, and in pmt, encoding a protein O-mannosyltransferase, are resistant to phage ϕC31 and have greatly increased susceptibility to some antibiotics, including vancomycin. In this work, second-site suppressors of the vancomycin susceptibility were isolated. The suppressor strains fell into two groups. Group 1 strains had increased resistance to vancomycin, teicoplanin and β-lactams, and had mutations in the two-component sensor regulator system encoded by vanSR, leading to upegulation of the vanSRJKHAX cluster. Group 2 strains only had increased resistance to vancomycin and these mostly had mutations in sco2592 or sco2593, genes that are derepressed in the presence of phosphate and are likely to be required for the synthesis of a phosphate-containing extracellular polymer. In some suppressor strains the increased resistance was only observed in media with limited phosphate (mimicking the phenotype of wild-type S. coelicolor), but two strains, DT3017_R21 (ppm1-vanR-) and DT3017_R15 (ppm1- sco2593-), retained resistance on media with high phosphate content. These results support the view that vancomycin resistance in S. coelicolor is a trade-off between mechanisms that confer resistance and at least one that interferes with resistance mediated through the sco2594-sco2593-sco2592 operon.