Lack of Antimicrobial Bactericidal Activity in Mycobacterium abscessus
Lack of Antimicrobial Bactericidal Activity in Mycobacterium abscessus
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DOI：
10.1128/aac.02448-14
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发表时间：
2014-07-01
影响因子：
4.9
通讯作者：
Boettger, Erik C.
中科院分区：
文献类型：
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作者：
Maurer, Florian P.;Bruderer, Vera L.;Boettger, Erik C.
由于新出现的病原体脓肿分枝杆菌对大多数临床可用的抗菌药物具有天然耐药性，因此抗生素治疗具有挑战性。我们研究了脓肿分枝杆菌感染中常用抗生素的杀菌活性，以便更好地了解不良的治疗结果。使用通常分类为杀菌（阿米卡星和莫西沙星）或抑菌（替加环素和利奈唑胺）的抗生素，生成临床脓肿分枝杆菌、耻垢分枝杆菌和大肠杆菌的时间杀灭曲线。此外，以耻垢分枝杆菌为模型生物，研究了氨基糖苷修饰酶对底物和非底物氨基糖苷类作用方式的影响。虽然阿米卡星和莫西沙星对大肠杆菌有杀菌作用，但没有一种测试化合物对脓肿分枝杆菌表现出杀菌活性。对耻垢分枝杆菌中氨基糖苷类作用模式的进一步机制研究表明，妥布霉素和庆大霉素的杀菌活性是通过破坏分枝杆菌基因组中的染色体aac(2')基因而恢复的。目前推荐的治疗方案中缺乏杀菌抗生素，这为脓肿分枝杆菌感染的治疗效果不佳提供了合理的解释。我们的研究结果表明，染色体编码的药物修饰酶在针对快速生长的分枝杆菌缺乏氨基糖苷类杀菌活性方面发挥着重要作用。
Antibiotic therapy of infections caused by the emerging pathogen Mycobacterium abscessus is challenging due to the organism's natural resistance toward most clinically available antimicrobials. We investigated the bactericidal activity of antibiotics commonly administered in M. abscessus infections in order to better understand the poor therapeutic outcome. Time-kill curves were generated for clinical M. abscessus isolates, Mycobacterium smegmatis, and Escherichia coli by using antibiotics commonly categorized as bactericidal (amikacin and moxifloxacin) or bacteriostatic (tigecycline and linezolid). In addition, the impact of aminoglycoside-modifying enzymes on the mode of action of substrate and nonsubstrate aminoglycosides was studied by using M. smegmatis as a model organism. While amikacin and moxifloxacin were bactericidal against E. coli, none of the tested compounds showed bactericidal activity against M. abscessus. Further mechanistic investigations of the mode of action of aminoglycosides in M. smegmatis revealed that the bactericidal activity of tobramycin and gentamicin was restored by disruption of the chromosomal aac(2') gene in the mycobacterial genome. The lack of bactericidal antibiotics in currently recommended treatment regimens provides a reasonable explanation for the poor therapeutic outcome in M. abscessus infection. Our findings suggest that chromosomally encoded drug-modifying enzymes play an important role in the lack of aminoglycoside bactericidal activity against rapidly growing mycobacteria.