Prophylactic Inhibition of Colonization by Streptococcus pneumoniae with the Secondary Bile Acid Metabolite Deoxycholic Acid.
Prophylactic Inhibition of Colonization by Streptococcus pneumoniae with the Secondary Bile Acid Metabolite Deoxycholic Acid.
复制标题
使用次级胆汁酸代谢物脱氧胆酸预防性抑制肺炎链球菌的定植。
DOI：
10.1128/iai.00463-21
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发表时间：
2021
影响因子：
3.1
通讯作者：
McDaniel,LarryS
中科院分区：
文献类型：
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作者：
Vidal,JorgeE;Wier,MeaganN;AAngulo-Zamudio,Uriel;McDevitt,Erin;JopVidal,AnaG;Alibayov,Babek;Scasny,Anna;Wong,SandyM;Akerley,BrianJ;McDaniel,LarryS
肺炎链球菌在儿童和老年人的鼻咽部定植，但每年也在全世界杀死数百万人。次级胆汁酸代谢产物脱氧胆酸（DoC）影响人类病原体的生存能力，但也在宿主生理学中发挥多种作用。我们在体外评估了DoC的抗菌活性，并研究了其根除沙门氏菌的潜力。使用人鼻咽定殖模型和动物体内小鼠定殖模型测定肺炎克雷伯氏菌定殖。在生理浓度下，DoC（0.5 mg/ml; 1.27 mM）杀死所有测试的S。pneumoniae菌株（n= 48）接种后2 h。鼻咽定殖模型显示，DoC可根除S. pneumoniae strains的表达。作用机制不涉及自溶激活，因为自溶缺陷双突变体ΔlytAΔ lytC和ΔspxBΔ lctO与野生型（WT）一样对DoC敏感。然而，口服链球菌物种（n= 20）对DoC（0.5 mg/ml）不敏感。与甲氧苄啶不同，TIGR 4或EF 3030的自发耐药频率（srF）≥1 × 10 - 9，DoC未观察到自发耐药（srF，≥1 × 10-12）。最后，观察了DoC根除S.通过鼻内（i.n.）给药和作为预防治疗。用S.接种后4天，肺炎EF 3030携带的中位数为4.05 × 105 CFU/ml，相比之下，用DoC处理的小鼠携带的中位数为6.67 × 104 CFU/ml。预防组小鼠的肺炎球菌密度（中位数，2.61 × 103 CFU/ml）降低了约99%。因此，DoC，一种内源性人胆汁盐，具有抗S.肺炎。
Streptococcus pneumoniae colonizes the nasopharynx of children and the elderly but also kills millions worldwide yearly. The secondary bile acid metabolite deoxycholic acid (DoC) affects the viability of human pathogens but also plays multiple roles in host physiology. We assessedin vitrothe antimicrobial activity of DoC and investigated its potential to eradicate S. pneumoniae colonization using a model of human nasopharyngeal colonization and anin vivomouse model of colonization. At a physiological concentration, DoC (0.5 mg/ml; 1.27 mM) killed all tested S. pneumoniae strains (n= 48) 2 h postinoculation. The model of nasopharyngeal colonization showed that DoC eradicated colonization by S. pneumoniae strains as soon as 10 min postexposure. The mechanism of action did not involve activation of autolysis, since the autolysis-defective double mutants ΔlytAΔlytCand ΔspxBΔlctOwere as susceptible to DoC as was the wild type (WT). Oral streptococcal species (n= 20), however, were not susceptible to DoC (0.5 mg/ml). Unlike trimethoprim, whose spontaneous resistance frequency (srF) for TIGR4 or EF3030 was ≥1 × 10−9, no spontaneous resistance was observed with DoC (srF, ≥1 × 10–12). Finally, the efficacy of DoC to eradicate S. pneumoniae colonization was assessedin vivousing a topical route via intranasal (i.n.) administration and as a prophylactic treatment. Mice challenged with S. pneumoniae EF3030 carried a median of 4.05 × 105CFU/ml 4 days postinoculation compared to 6.67 × 104CFU/ml for mice treated with DoC. Mice in the prophylactic group had an ∼99% reduction of the pneumococcal density (median, 2.61 × 103CFU/ml). Thus, DoC, an endogenous human bile salt, has therapeutic potential against S. pneumoniae.