Antibiotic modulation of capsular exopolysaccharide and virulence in Acinetobacter baumannii.
Antibiotic modulation of capsular exopolysaccharide and virulence in Acinetobacter baumannii.
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DOI：
10.1371/journal.ppat.1004691
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发表时间：
2015-02
期刊：
影响因子：
6.7
通讯作者：
Isberg RR
中科院分区：
文献类型：
--
作者：
Geisinger E;Isberg RR
鲍曼不动杆菌是一种越来越重要的机会致病菌，由于其在医院中的难治性多药耐药感染的倾向。所有临床分离株检查包含一个保守的基因簇，K基因座，它决定了复杂的多糖，包括一个外多糖胶囊，已知保护免受宿主血清杀死，并增加在动物模型中的毒力感染的生产。由K基因座决定的多糖是否有助于对抗生素的内在防御尚不清楚。我们在这里证明，突变体缺乏胞外多糖胶囊降低了固有的耐肽抗生素，而突变影响糖前体参与胶囊和脂多糖合成敏感的细菌多种抗生素类。我们观察到，当在低于其MIC的某些抗生素存在下生长时，包括翻译抑制剂氯霉素和红霉素，A.鲍曼不动杆菌增加了K基因座胞外多糖的产生。荚膜外多糖的过度产生是可逆的和非突变的，并且伴随着对诱导抗生素的耐药性增加而发生，这与K基因座的存在无关。引人注目的是，在全身感染的小鼠模型中，抗寄生虫增强的荚膜外多糖产生赋予对宿主补体杀伤的增加的抗性并增加毒力。最后，我们表明，增强胶囊生产抗生素暴露后，促进K基因座基因表达的转录增加，依赖于一个双组分调控系统，bfmRS。这些研究表明，荚膜的合成，一个主要的致病性决定因素，是在响应抗生素胁迫调节。我们的数据与抗生素治疗无效引起的基因表达变化导致A。鲍曼不动杆菌在低和高毒力潜力状态之间转换，这可能有助于病原体的机会性。 鲍曼不动杆菌作为医院获得性感染的原因而声名狼借，由于广泛的抗生素耐药性而难以治疗。虽然这种微生物很少在社区引起疾病，但它通常会感染接受抗生素治疗的患者。细菌在抗生素存在下能够生长的内在因素尚未得到很好的表征。此外，亚抑菌抗生素浓度对A.鲍曼不动杆菌病未知。在这里，我们研究了K基因座，一种负责产生保护性表面多糖的细菌疾病决定因素，并询问该决定因素是否也有助于抗生素耐药性。我们发现K基因座多糖促进对多种抗生素的抗性，并且出乎意料地，细菌通过增加主要K基因座多糖胶囊的产生来响应亚抑制浓度的某些抗生素。这种通过上调K基因座基因表达介导的胶囊的增加的产生，增加了细菌克服补体系统攻击的能力，补体系统是一种重要的抗病原体宿主防御，并在小鼠实验性血流感染期间导致致命疾病。研究表明，A.在抗生素治疗不充分的情况下，鲍曼不动杆菌的致病潜力增加，这可能促进机会性感染的发展。
Acinetobacter baumannii is an opportunistic pathogen of increasing importance due to its propensity for intractable multidrug-resistant infections in hospitals. All clinical isolates examined contain a conserved gene cluster, the K locus, which determines the production of complex polysaccharides, including an exopolysaccharide capsule known to protect against killing by host serum and to increase virulence in animal models of infection. Whether the polysaccharides determined by the K locus contribute to intrinsic defenses against antibiotics is unknown. We demonstrate here that mutants deficient in the exopolysaccharide capsule have lowered intrinsic resistance to peptide antibiotics, while a mutation affecting sugar precursors involved in both capsule and lipopolysaccharide synthesis sensitizes the bacterium to multiple antibiotic classes. We observed that, when grown in the presence of certain antibiotics below their MIC, including the translation inhibitors chloramphenicol and erythromycin, A. baumannii increases production of the K locus exopolysaccharide. Hyperproduction of capsular exopolysaccharide is reversible and non-mutational, and occurs concomitantly with increased resistance to the inducing antibiotic that is independent of the presence of the K locus. Strikingly, antibiotic-enhanced capsular exopolysaccharide production confers increased resistance to killing by host complement and increases virulence in a mouse model of systemic infection. Finally, we show that augmented capsule production upon antibiotic exposure is facilitated by transcriptional increases in K locus gene expression that are dependent on a two-component regulatory system, bfmRS. These studies reveal that the synthesis of capsule, a major pathogenicity determinant, is regulated in response to antibiotic stress. Our data are consistent with a model in which gene expression changes triggered by ineffectual antibiotic treatment cause A. baumannii to transition between states of low and high virulence potential, which may contribute to the opportunistic nature of the pathogen. Acinetobacter baumannii has gained notoriety as a cause of hospital-acquired infections that are difficult to treat due to extensive antibiotic resistance. While the microorganism rarely causes disease in the community, it commonly infects patients receiving antibiotics. The factors intrinsic to the bacterium that enable growth in the presence of antibiotics are not well characterized. Furthermore, the consequences of subinhibitory antibiotic concentrations on A. baumannii disease are unknown. Here we examined the K locus, a bacterial disease determinant responsible for the production of protective surface polysaccharides, and asked whether this determinant also contributes to antibiotic resistance. We found that K locus polysaccharides facilitate resistance to multiple antibiotics, and, unexpectedly, that the bacterium responds to certain antibiotics at subinhibitory concentrations by increasing production of capsule, the principal K locus polysaccharide. This augmented production of capsule, which is mediated by upregulation of K locus gene expression, increased the ability of the bacterium to overcome attack by the complement system, an important anti-pathogen host defense, and result in lethal disease during experimental bloodstream infection in mice. Our studies indicate that A. baumannii increases its disease-causing potential in the setting of inadequate antibiotic treatment, which may promote the development of opportunistic infections.
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影响因子：
3.1
作者：
Breslow, Jessica M.;Meissler, Joseph J., Jr.;Eisenstein, Toby K.
通讯作者：
Eisenstein, Toby K.
影响因子：
3.1
作者：
Fregolino, Eleonora;Gargiulo, Valentina;De Castro, Cristina
通讯作者：
De Castro, Cristina
影响因子：
11.8
作者：
Boucher, Helen W.;Talbot, George H.;Bartlett, John
通讯作者：
Bartlett, John
DOI：
10.1002/path.1700630413
发表时间：
1951-01-01
期刊：
JOURNAL OF PATHOLOGY AND BACTERIOLOGY
影响因子：
--
作者：
DUGUID, JP
通讯作者：
DUGUID, JP
影响因子：
4.5
作者：
Hidron, Alicia I.;Edwards, Jonathan R.;Fridkin, Scott K.
通讯作者：
Fridkin, Scott K.