Amixicile depletes the ex vivo periodontal microbiome of anaerobic bacteria.
Amixicile depletes the ex vivo periodontal microbiome of anaerobic bacteria.
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DOI：
10.1016/j.job.2020.03.004
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发表时间：
2020-06
影响因子：
2.4
通讯作者：
Lewis JP
中科院分区：
文献类型：
--
作者：
Gui Q;Ramsey KW;Hoffman PS;Lewis JP
虽然牙周病是由厌氧菌的过度生长引起的，但厌氧菌的特定敲除对疾病结果的影响还有待研究。我们已经报道，amixicile，一种无毒，易于生物利用的新型抗菌剂，通过抑制丙酮酸铁氧还蛋白氧化还原酶（PFOR）（一种介导丙酮酸氧化脱羧的主要酶）的活性，特异性靶向选定的口腔厌氧菌。在这里，我们生成了一个来自慢性牙周病患者牙龈袋的离体微生物组，并评估了amixicile在产生微生物组中存在的厌氧菌的特异性敲除方面的功效。我们的生物信息学分析确定了PFO样编码能力，在100多个基因组可从HOMD数据库。其中许多细菌存在于我们的体外微生物组中。值得注意的是，依赖PFOR产生能量的厌氧病原体在用amixicile处理后丰度明显减少，而非PFOR细菌则幸免于难。具体而言，普雷沃氏菌、韦荣氏菌、斯拉奇氏菌、卟啉单胞菌、密螺旋体、大隐球菌和阿托菌的丰度减少。这种治疗导致类似于来自牙周病部位的微生物组的微生物组转化为类似于健康部位存在的微生物组的微生物组。我们还比较了阿莫西莱和甲硝唑的抑菌谱，结果表明这两种抗生素具有相似的抑菌谱。这项工作进一步表明，amixicile有可能逆转和防止在牙周病受试者中观察到的厌氧病原体的生长。阿莫西莱抑制厌氧菌的机制示意图。含有丙酮酸盐：铁氧还蛋白氧化还原酶（PFOR [KEGG：1.2.7.1]）的细菌显示为红色，依赖丙酮酸脱氢酶（PDH [KEGG：1.2.4.1]）的耐氧细菌显示为蓝色。
Although periodontal diseases result from overgrowth of anaerobic bacteria, the effect of a specific knockdown of anaerobes on the disease outcome has yet to be examined. We have reported that amixicile, a non-toxic, readily bioavailable, and novel antimicrobial, specifically targets selected oral anaerobes through inhibition of the activity of pyruvate ferredoxin oxidoreductase (PFOR), a major enzyme mediating oxidative decarboxylation of pyruvate. Here, we generated an ex vivo microbiome derived from gingival pockets of human subjects with chronic periodontal disease and evaluated the efficacy of amixicile in generating a specific knockdown of anaerobic bacteria present in the microbiome. Our bioinformatics analysis identified PFOR-like coding capacity in over 100 genomes available from the HOMD database. Many of those bacteria were present in our ex vivo microbiome. Significantly, the anaerobic pathogens relying on PFOR for energy generation were specifically reduced in abundance following treatment with amixicile while non-PFOR bacteria were spared. Specifically, Prevotella, Veillonella, Slackia, Porphyromonas, Treponema, Megasphera, and Atobium were reduced in abundance. Such treatment resulted in the conversion of a microbiome resembling a microbiome derived from sites with periodontal disease to one resembling a microbiome present at healthy sites. We also compared the inhibitory spectrum of amixicile to that of metronidazole and showed that the antibiotics have a similar inhibitory spectrum. This work further demonstrates that amixicile has the potential to reverse and prevent the outgrowth of anaerobic pathogens observed in subjects with periodontal disease. Schematic representation of the mechanism of amixicile leading to inhibition of anaerobic bacteria. Pyruvate:ferredoxin oxidoreductase (PFOR [KEGG: 1.2.7.1]) - containing bacteria are shown in red and aerotolerant bacteria, relying on pyruvate dehydrogenase (PDH [KEGG: 1.2.4.1]), are shown in blue.
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影响因子：
11
作者：
Duran-Pinedo, Ana E.;Chen, Tsute;Frias-Lopez, Jorge
通讯作者：
Frias-Lopez, Jorge
影响因子：
15.5
作者：
Edlund A;Yang Y;Hall AP;Guo L;Lux R;He X;Nelson KE;Nealson KH;Yooseph S;Shi W;McLean JS
通讯作者：
McLean JS
影响因子：
48
作者：
Segata, Nicola;Waldron, Levi;Ballarini, Annalisa;Narasimhan, Vagheesh;Jousson, Olivier;Huttenhower, Curtis
通讯作者：
Huttenhower, Curtis
影响因子：
14.9
作者：
Markowitz VM;Chen IM;Palaniappan K;Chu K;Szeto E;Pillay M;Ratner A;Huang J;Woyke T;Huntemann M;Anderson I;Billis K;Varghese N;Mavromatis K;Pati A;Ivanova NN;Kyrpides NC
通讯作者：
Kyrpides NC
影响因子：
3.5
作者：
Califano, JV;Arimoto, T;Kitten, T
通讯作者：
Kitten, T