Department of Clinical Microbiology 9301, Rigshospitalet, Copenhagen, Denmark.
The Novo Nordisk Foundation Center for Biosustainability, Technical University of Denmark, Kgs. Lyngby, Denmark.
Nat Commun. 2024 Mar 22;15(1):2584. doi: 10.1038/s41467-024-46938-w.
Mutations in mexZ, encoding a negative regulator of the expression of the mexXY efflux pump genes, are frequently acquired by Pseudomonas aeruginosa at early stages of lung infection. Although traditionally related to resistance to the first-line drug tobramycin, mexZ mutations are associated with low-level aminoglycoside resistance when determined in the laboratory, suggesting that their selection during infection may not be necessarily, or only, related to tobramycin therapy. Here, we show that mexZ-mutated bacteria tend to accumulate inside the epithelial barrier of a human airway infection model, thus colonising the epithelium while being protected against diverse antibiotics. This phenotype is mediated by overexpression of lecA, a quorum sensing-controlled gene, encoding a lectin involved in P. aeruginosa tissue invasiveness. We find that lecA overexpression is caused by a disrupted equilibrium between the overproduced MexXY and another efflux pump, MexAB, which extrudes quorum sensing signals. Our results indicate that mexZ mutations affect the expression of quorum sensing-regulated pathways, thus promoting tissue invasiveness and protecting bacteria from the action of antibiotics within patients, something unnoticeable using standard laboratory tests.
mexZ 基因突变，编码MexXY 外排泵基因表达的负调控因子，在铜绿假单胞菌肺部感染的早期阶段经常获得。尽管传统上与对一线药物妥布霉素的耐药性有关，但 mexZ 突变与实验室确定的低水平氨基糖苷类耐药性相关，这表明它们在感染过程中的选择不一定或仅与妥布霉素治疗有关。在这里，我们表明 mexZ 突变的细菌往往在人类气道感染模型的上皮屏障内积累，从而在受到多种抗生素的保护的同时定植在上皮组织中。这种表型是由 LecA 的过表达介导的，LecA 是一种群体感应控制的基因，编码一种参与铜绿假单胞菌组织侵袭的凝集素。我们发现 LecA 的过表达是由过度产生的 MexXY 和另一种外排泵 MexAB 之间的失衡引起的，MexAB 会排出群体感应信号。我们的结果表明，mexZ 突变会影响群体感应调控途径的表达，从而促进组织侵袭，并保护细菌免受患者体内抗生素的作用，这在使用标准实验室检测时是无法察觉的。
