Centro Nacional de Biotecnología, CSIC, Madrid, Spain.
J Antimicrob Chemother. 2019 Nov 1;74(11):3221-3230. doi: 10.1093/jac/dkz326.
To elucidate the potential mutation-driven mechanisms involved in the acquisition of tigecycline resistance by the opportunistic pathogen Stenotrophomonas maltophilia. The mutational trajectories and their effects on bacterial fitness, as well as cross-resistance and/or collateral susceptibility to other antibiotics, were also addressed.
S. maltophilia populations were submitted to experimental evolution in the presence of increasing concentrations of tigecycline for 30 days. The genetic mechanisms involved in the acquisition of tigecycline resistance were determined by WGS. Resistance was evaluated by performing MIC assays. Fitness of the evolved populations and individual clones was assessed by measurement of the maximum growth rates.
All the tigecycline-evolved populations attained high-level resistance to tigecycline following different mutational trajectories, yet with some common elements. Among the mechanisms involved in low susceptibility to tigecycline, mutations in the SmeDEF efflux pump negative regulator smeT, changes in proteins involved in the biogenesis of the ribosome and modifications in the LPS biosynthesis pathway seem to play a major role. Besides tigecycline resistance, the evolved populations presented cross-resistance to other antibiotics, such as aztreonam and quinolones, and they were hypersusceptible to fosfomycin, suggesting a possible combination treatment. Further, we found that the selected resistance mechanisms impose a relevant fitness cost when bacteria grow in the absence of antibiotic.
Mutational resistance to tigecycline was easily selected during exposure to this antibiotic. However, the fitness cost may compromise the maintenance of S. maltophilia tigecycline-resistant populations in the absence of antibiotic.
阐明机会性病原体嗜麦芽寡养单胞菌获得替加环素耐药性的潜在突变驱动机制。还研究了突变轨迹及其对细菌适应性的影响，以及对其他抗生素的交叉耐药性和/或附带敏感性。
将嗜麦芽寡养单胞菌种群在替加环素浓度逐渐增加的情况下进行 30 天的实验进化。通过 WGS 确定获得替加环素耐药性的遗传机制。通过进行 MIC 测定来评估耐药性。通过测量最大生长速率来评估进化种群和单个克隆的适应性。
所有经替加环素进化的种群在不同的突变轨迹下均获得了高水平的替加环素耐药性，但具有一些共同的特征。在对替加环素低敏感性的机制中，SmeDEF 外排泵负调节剂 smeT 的突变、核糖体生物发生过程中涉及的蛋白质的变化以及 LPS 生物合成途径的修饰似乎起着重要作用。除了对替加环素的耐药性外，进化后的种群还表现出对其他抗生素（如氨曲南和喹诺酮类药物）的交叉耐药性，并且对磷霉素高度敏感，表明可能存在联合治疗。此外，我们发现，所选的耐药机制在没有抗生素的情况下生长时会给细菌带来相当大的适应性成本。
在接触这种抗生素时，很容易选择突变性的替加环素耐药性。然而，适应性成本可能会影响嗜麦芽寡养单胞菌替加环素耐药菌在没有抗生素的情况下的维持。
