Induction of Daptomycin Tolerance in Enterococcus faecalis by Fatty Acid Combinations.
Induction of Daptomycin Tolerance in Enterococcus faecalis by Fatty Acid Combinations.
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DOI：
10.1128/aem.01178-20
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发表时间：
2020-10-01
影响因子：
4.4
通讯作者：
Fozo EM
中科院分区：
文献类型：
--
作者：
Brewer W;Harrison J;Saito HE;Fozo EM
随着抗生素耐药性在临床上的日益流行，我们努力了解更多关于微生物防御机制的知识。在粪肠球菌中发现了对抗生素达托霉素的非遗传耐受性，导致使用该药物治疗后细菌种群的存活率增加。这种耐受机制可能与临床上的抗生素耐药性协同作用。考虑到这种耐受性表型是由宿主中存在的脂肪酸诱导的，可以假设这种微生物的感染需要更高剂量的抗生素才能成功根除。人体体液中的脂肪酸混合物相当多样，对脂肪酸组合的相互作用和我们观察到的耐受表型之间的相互作用知之甚少。如果我们要在临床上抑制粪肠球菌的耐受生理，了解脂肪酸组合对粪肠球菌生理的影响是至关重要的。粪肠球菌是一种革兰氏阳性细菌，通常以肠道共生形式存在于人类体内，但也是医院感染的主要原因。以前的工作指出，补充血清的生长会诱导对膜损伤剂的耐受性，包括抗生素达托霉素。血清中发现的特定脂肪酸可以独立地提供对达托霉素的耐受性(保护性脂肪酸)，但血清中发现的一些脂肪酸不能提供耐受性，并对肠球菌的生理产生负面影响(非保护性脂肪酸)。在这里，我们测量了补充保护性和非保护性脂肪酸组合后的广泛的生理反应，以更好地了解血清如何诱导达托霉素耐受。当添加非保护性脂肪酸、棕榈酸或硬脂酸时，细胞在生长和形态上有明显的缺陷，但当补充保护性脂肪酸、油酸或亚油酸时，这些缺陷被挽救。膜流动性在棕榈酸或硬脂酸单独作用下随生长而降低，但当提供保护性脂肪酸时，膜流动性恢复到基础水平。如果保护性脂肪酸与非保护性脂肪酸一起提供，并保护某些特定的组合以及补充血清，则可诱导达托霉素耐受。虽然细胞包膜电荷与其他革兰氏阳性细菌对达托霉素的耐受性有关，但我们得出的结论是，它与我们观察到的脂肪酸诱导的保护无关。基于这些观察，我们得出结论，血清对达托霉素的耐受是由液体中发现的特定的保护性脂肪酸驱动的。重要性随着抗生素耐药性在临床上的日益普遍，我们努力更多地了解微生物的防御机制。在粪肠球菌中发现了对抗生素达托霉素的非遗传耐受性，导致使用该药物治疗后细菌种群的存活率增加。这种耐受机制可能与临床上的抗生素耐药性协同作用。考虑到这种耐受性表型是由宿主中存在的脂肪酸诱导的，可以假设这种微生物的感染需要更高剂量的抗生素才能成功根除。人体体液中的脂肪酸混合物相当多样，对脂肪酸组合的相互作用和我们观察到的耐受表型之间的相互作用知之甚少。如果我们要在临床上抑制粪肠球菌的耐受生理，了解脂肪酸组合对粪肠球菌生理的影响是至关重要的。
With an increasing prevalence of antibiotic resistance in the clinic, we strive to understand more about microbial defensive mechanisms. A nongenetic tolerance to the antibiotic daptomycin was discovered in Enterococcus faecalis that results in the increased survival of bacterial populations after treatment with the drug. This tolerance mechanism likely synergizes with antibiotic resistance in the clinic. Given that this tolerance phenotype is induced by incorporation of fatty acids present in the host, it can be assumed that infections by this organism require a higher dose of antibiotic for successful eradication. The mixture of fatty acids in human fluids is quite diverse, with little understanding between the interplay of fatty acid combinations and the tolerance phenotype we observe. It is crucial to understand the effects of fatty acid combinations on E. faecalis physiology if we are to suppress the tolerance physiology in the clinic. Enterococcus faecalis is a Gram-positive bacterium that normally exists as an intestinal commensal in humans but is also a leading cause of nosocomial infections. Previous work noted that growth supplementation with serum induced tolerance to membrane-damaging agents, including the antibiotic daptomycin. Specific fatty acids found within serum could independently provide tolerance to daptomycin (protective fatty acids), yet some fatty acids found in serum did not and had negative effects on enterococcal physiology (nonprotective fatty acids). Here, we measured a wide array of physiological responses after supplementation with combinations of protective and nonprotective fatty acids to better understand how serum induces daptomycin tolerance. When cells were supplemented with either nonprotective fatty acid, palmitic acid, or stearic acid, there were marked defects in growth and morphology, but these defects were rescued upon supplementation with either protective fatty acid, oleic acid, or linoleic acid. Membrane fluidity decreased with growth in either palmitic or stearic acid alone but returned to basal levels when a protective fatty acid was supplied. Daptomycin tolerance could be induced if a protective fatty acid was provided with a nonprotective fatty acid, and some specific combinations protected as well as serum supplementation. While cell envelope charge has been associated with tolerance to daptomycin in other Gram-positive bacteria, we concluded that it does not correlate with the fatty acid-induced protection we observed. Based on these observations, we conclude that daptomycin tolerance by serum is driven by specific, protective fatty acids found within the fluid. IMPORTANCE With an increasing prevalence of antibiotic resistance in the clinic, we strive to understand more about microbial defensive mechanisms. A nongenetic tolerance to the antibiotic daptomycin was discovered in Enterococcus faecalis that results in the increased survival of bacterial populations after treatment with the drug. This tolerance mechanism likely synergizes with antibiotic resistance in the clinic. Given that this tolerance phenotype is induced by incorporation of fatty acids present in the host, it can be assumed that infections by this organism require a higher dose of antibiotic for successful eradication. The mixture of fatty acids in human fluids is quite diverse, with little understanding between the interplay of fatty acid combinations and the tolerance phenotype we observe. It is crucial to understand the effects of fatty acid combinations on E. faecalis physiology if we are to suppress the tolerance physiology in the clinic.