Stepwise exposure of Staphylococcus aureus to pleuromutilins is associated with stepwise acquisition of mutations in rplC and minimally affects susceptibility to retapamulin
Stepwise exposure of Staphylococcus aureus to pleuromutilins is associated with stepwise acquisition of mutations in rplC and minimally affects susceptibility to retapamulin
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DOI：
10.1128/aac.01066-06
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发表时间：
2007-06-01
影响因子：
4.9
通讯作者：
Holmes, David J.
中科院分区：
文献类型：
--
作者：
Gentry, Daniel R.;Rittenhouse, Stephen F.;Holmes, David J.
为了评估它们对金黄色葡萄球菌中瑞他莫林敏感性的影响，分离出对泰妙菌素和其他研究截短侧耳素化合物具有升高MIC的第一步、第二步和第三步突变体，并通过暴露于高药物浓度进行表征。所有第一步和第二步突变都在rplC中，编码核糖体蛋白L3。大多数第三步突变体在rplC中获得第三突变。虽然第一步和第二步突变确实导致泰妙林和瑞他莫林MIC升高，但直到获得第三次突变才观察到活性显著降低。所有的第三步突变体表现出严重的生长缺陷，和快速增长的变种出现在高频率从大多数菌株。发现这些生长较快的变体对截短侧耳素更敏感。在rplC中具有三个改变的突变体的情况下，快速生长的变体获得rplC中的另外的突变。在rplC中具有两个突变并且在未定位的基因座处具有至少一个突变的分离株的快速生长变体的情况下，两个rplC突变中的一个恢复为野生型。这些数据表明，导致截短侧耳素抗性的rplC突变对适应性具有直接的负面影响。瑞他帕林对S.金黄色葡萄球菌的耐药性可以通过rplC中的突变来观察，很可能对瑞他帕林的靶特异性耐药性将缓慢出现，这是由于需要三个突变来显著影响活性和每个突变步骤的适应性成本。
To assess their effects on susceptibility to retapamulin in Staphylococcus aureus, first-, second-, and third-step mutants with elevated MICs to tiamulin and other investigational pleuromutilin compounds were isolated and characterized through exposure to high drug concentrations. All first- and second-step mutations were in rplC, encoding ribosomal protein L3. Most third-step mutants acquired a third mutation in rplC. While first- and second-step mutations did cause an elevation in tiamulin and retapamulin MICs, a significant decrease in activity was not seen until a third mutation was acquired. All third-step mutants exhibited severe growth defects, and faster-growing variants arose at a high frequency from most isolates. These faster-growing variants were found to be more susceptible to pleuromutilins. In the case of a mutant with three alterations in rplC, the fast-growing variants acquired an additional mutation in rplC. In the case of fast-growing variants of isolates with two mutations in rplC and at least one mutation at an unmapped locus, one of the two rplC mutations reverted to wild type. These data indicate that mutations in rplC that lead to pleuromutilin resistance have a direct, negative effect on fitness. While reduction in activity of retapamulin against S. aureus can be seen through mutations in rplC, it is likely that target-specific resistance to retapamulin will be slow to emerge due to the need for three mutations for a significant effect on activity and the fitness cost of each mutational step.