High-level carbapenem tolerance requires antibiotic-induced outer membrane modifications.
High-level carbapenem tolerance requires antibiotic-induced outer membrane modifications.
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DOI：
10.1371/journal.ppat.1010307
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发表时间：
2022-03
期刊：
影响因子：
6.7
通讯作者：
Dörr T
中科院分区：
文献类型：
--
作者：
Murtha AN;Kazi MI;Schargel RD;Cross T;Fihn C;Cattoir V;Carlson EE;Boll JM;Dörr T
抗生素耐受性是抗生素治疗失败和多重耐药细菌出现的一个未充分研究的潜在因素。对控制耐受性的分子机制仍然知之甚少。一种突出类型的β-内酰胺耐受性依赖于细胞壁缺陷型原生质球的形成，其通过其外膜（OM）、由内小叶上的磷脂组成的不对称脂质双层和在细胞表面上的外单层中富集的脂质连接的多糖（脂多糖，LPS）保持结构完整性。像LPS这样的膜结构仅依赖静电相互作用来维持稳定性，如何能够对抗内部膨压尚不清楚。在这里，我们发现了PhoPQ双组分系统在肠球菌目中对β-内酰胺抗生素美罗培南的耐受性中的新作用。我们发现PhoPQ是由美罗培南处理诱导的，并促进脂A（LPS的膜锚）的4-氨基-4-脱氧-L-氨基阿拉伯糖[L-Ara 4 N]修饰的增加。L-Ara 4 N修饰可能增强结构完整性，并因此增强对美罗培南的耐受性，在几个肠球菌目物种中。重要的是，突变失活的负PhoPQ调节mgrB（通常选择在临床治疗的最后手段抗生素粘菌素，抗菌肽[AMP]）的结果显着增强的耐受性，这表明AMP可以通过稳定的过度激活PhoPQ间接选择美罗培南耐受性。最后，我们确定了组氨酸激酶抑制剂（包括FDA批准的药物），抑制PhoPQ依赖性LPS修饰，从而增强美罗培南，以提高耐受细胞的溶解。总之，我们的研究结果表明，PhoPQ介导的LPS修饰在稳定OM方面发挥着重要作用，当主要的完整性维持结构（细胞壁）被去除时，促进存活。用抗生素治疗感染往往失败，导致巨大的公共卫生负担。治疗失败的一个未充分研究的可能原因是“抗生素耐受性”的发展，即细菌在通常致命的抗生素暴露下存活的能力。在这里，我们描述了一种促进耐受性的分子机制。细菌应激传感器（PhoPQ）响应于抗生素（美罗培南）处理而被激活，从而加强细菌保护性“壳”以提高存活率。我们还确定了这种机制的抑制剂，为开发有助于抗生素更好地对抗耐受细菌的化合物打开了大门。
Antibiotic tolerance is an understudied potential contributor to antibiotic treatment failure and the emergence of multidrug-resistant bacteria. The molecular mechanisms governing tolerance remain poorly understood. A prominent type of β-lactam tolerance relies on the formation of cell wall-deficient spheroplasts, which maintain structural integrity via their outer membrane (OM), an asymmetric lipid bilayer consisting of phospholipids on the inner leaflet and a lipid-linked polysaccharide (lipopolysaccharide, LPS) enriched in the outer monolayer on the cell surface. How a membrane structure like LPS, with its reliance on mere electrostatic interactions to maintain stability, is capable of countering internal turgor pressure is unknown. Here, we have uncovered a novel role for the PhoPQ two-component system in tolerance to the β-lactam antibiotic meropenem in Enterobacterales. We found that PhoPQ is induced by meropenem treatment and promotes an increase in 4-amino-4-deoxy-L-aminoarabinose [L-Ara4N] modification of lipid A, the membrane anchor of LPS. L-Ara4N modifications likely enhance structural integrity, and consequently tolerance to meropenem, in several Enterobacterales species. Importantly, mutational inactivation of the negative PhoPQ regulator mgrB (commonly selected for during clinical therapy with the last-resort antibiotic colistin, an antimicrobial peptide [AMP]) results in dramatically enhanced tolerance, suggesting that AMPs can collaterally select for meropenem tolerance via stable overactivation of PhoPQ. Lastly, we identify histidine kinase inhibitors (including an FDA-approved drug) that inhibit PhoPQ-dependent LPS modifications and consequently potentiate meropenem to enhance lysis of tolerant cells. In summary, our results suggest that PhoPQ-mediated LPS modifications play a significant role in stabilizing the OM, promoting survival when the primary integrity maintenance structure, the cell wall, is removed. Treating an infection with an antibiotic often fails, resulting in a tremendous public health burden. One understudied likely reason for treatment failure is the development of “antibiotic tolerance”, the ability of bacteria to survive normally lethal exposure to an antibiotic. Here, we describe a molecular mechanism promoting tolerance. A bacterial stress sensor (PhoPQ) is activated in response to antibiotic (meropenem) treatment and consequently strengthens a bacterial protective “shell” to enhance survival. We also identify inhibitors of this mechanism, opening the door to developing compounds that help antibiotics work better against tolerant bacteria.
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影响因子：
28.3
作者：
Band, Victor I.;Crispell, Emily K.;Napier, Brooke A.;Herrera, Carmen M.;Tharp, Greg K.;Vavikolanu, Kranthi;Pohl, Jan;Read, Timothy D.;Bosinger, Steven E.;Trent, M. Stephen;Burd, Eileen M.;Weiss, David S.
通讯作者：
Weiss, David S.
DOI：
10.1073/pnas.1611594113
发表时间：
2016-10-11
影响因子：
11.1
作者：
Boll, Joseph M.;Crofts, Alexander A.;Trent, M. Stephen
通讯作者：
Trent, M. Stephen
影响因子：
3.6
作者：
Gunn, JS;Lim, KB;Miller, SI
通讯作者：
Miller, SI
影响因子：
48
作者：
Gibson, Daniel G.;Young, Lei;Smith, Hamilton O.
通讯作者：
Smith, Hamilton O.
影响因子：
6.7
作者：
Band, Victor I.;Weiss, David S.
通讯作者：
Weiss, David S.