Polyamine effects on antibiotic susceptibility in bacteria
Polyamine effects on antibiotic susceptibility in bacteria
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DOI：
10.1128/aac.01472-06
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发表时间：
2007-06-01
影响因子：
4.9
通讯作者：
Lu, Chung-Dar
中科院分区：
文献类型：
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作者：
Kwon, Dong-Hyeon;Lu, Chung-Dar
生物多胺（例如，亚精胺和精胺）是在所有活细胞中发现的一组必需的聚阳离子化合物。用革兰氏阴性大肠杆菌、鼠伤寒沙门氏菌、铜绿假单胞菌临床分离株和革兰氏阳性金黄色葡萄球菌（包括耐甲氧西林金黄色葡萄球菌）检测精胺和亚精胺对抗生素敏感性的影响。金黄色葡萄球菌（MRSA）。外源精胺对大肠杆菌的生长具有剂量依赖性抑制作用。coli、S.和S.如MIC和生长曲线测量所示，金黄色葡萄球菌而不是铜绿假单胞菌。外源性精胺和亚精胺对铜绿假单胞菌的多粘菌素和环丙沙星的MIC均显著升高，但对肠道细菌和S.金黄色。发现精胺和亚精胺可以以菌株依赖性方式降低所有菌株中β-内酰胺类抗生素以及其他类型抗生素的MIC。值得注意的是，在精胺存在下，苯唑西林对MRSA Mu 50和N315的MIC降低了200倍以上，当在二价离子（镁或钙; 3 mM）或氯化钠（150 mM）存在下进行评估时，精胺的这种作用得以保留。通过群体分析和时间杀灭试验进一步证实精胺对铜绿假单胞菌和MRSA对抗生素的致敏作用。用E. coli和革兰氏阳性菌S.金黄色葡萄球菌显示了精胺与β-内酰胺和氯霉素组合的强协同作用。β-内酰胺类药物的MIC降低表明外源性精胺或亚精胺对外膜孔蛋白的可能阻断在大多数情况下并不起关键作用。相比之下，外源精胺和亚精胺仅增加亚胺培南对铜绿假单胞菌的MIC，并且在缺失外膜孔蛋白OprD的突变菌株中消除了这种耐药作用。在大肠大肠杆菌中，羧苄青霉素、氯霉素和四环素的MIC在两个缺失主要外排泵AcrAB的acrA突变体中降低。然而，在两个大肠杆菌acrA突变体中，精胺对抗生素敏感性的影响仍然存在。提示AcrAB外排泵不是精胺与抗生素协同作用的靶点，排除了精胺作为外排泵抑制剂的可能性。总之，精胺对抗生素敏感性影响这一有趣的发现为利用现有的β-内酰胺类抗生素对抗耐药病原体的新的潜在方法提供了基础。
Biogenic polyamines (e.g., spermidine and spermine) are a group of essential polycationic compounds found in all living cells. The effects of spermine and spermidine on antibiotic susceptibility were examined with gram-negative Escherichia coli and Salmonella enterica serovar Typhimurium bacteria and clinical isolates of Pseudomonas aeruginosa and with gram-positive Staphylococcus aureus bacteria, including methicillin-resistant S. aureus (MRSA). Exogenous spermine exerted a dose-dependent inhibition effect on the growth of E. coli, S. enterica serovar Typhimurium, and S. aureus but not P. aeruginosa, as depicted by MIC and growth curve measurements. While the MICs of polymyxin and ciprofloxacin were in general increased by exogenous spermine and spermidine in P. aeruginosa, this adverse effect was not observed in enteric bacteria and S. aureus. It was found that spermine and spermidine can decrease the MICs of beta-lactam antibiotics in all strains as well as other types of antibiotics in a strain-dependent manner. Significantly, the MICs of oxacillin for MRSA Mu50 and N315 were decreased more than 200-fold in the presence of spermine, and this effect of spermine was retained when assessed in the presence of divalent ions (magnesium or calcium; 3 mM) or sodium chloride (150 mM). The effect of spermine on the sensitization of P. aeruginosa and MRSA to antibiotics was further demonstrated by population analysis and time-killing assays. The results of checkerboard assays with E. coli and S. aureus indicated a strong synergistic effect of spermine in combination with beta-lactams and chloramphenicol. The decreased MICs of beta-lactams implied that the possible blockage of outer membrane porins by exogenous spermine or spermidine did not play a crucial role in most cases. In contrast, only the MIC of imipenem against P. aeruginosa was increased by exogenous spermine and spermidine, and this resistance effect was abolished in a mutant strain devoid of the outer membrane porin OprD. In E. coli, the MICs of carbenicillin, chloramphenicol, and tetracycline were decreased in two acrA mutants devoid of a major efflux pump, AcrAB. However, retention of the spermine effect on antibiotic susceptibility in two acrA mutants of E. coli suggested that the AcrAB efflux pump was not the target for a synergistic effect by spermine and antibiotics and ruled out the hypothesis of spermine serving as an efflux pump inhibitor in this organism. In summary, this interesting finding of the effect of spermine on antibiotic susceptibility provides the basis for a new potential approach against drug-resistant pathogens by use of existing beta-lactam antibiotics.