Resistance Evolution Against Antimicrobial Peptides in Staphylococcus aureus Alters Pharmacodynamics Beyond the MIC
Resistance Evolution Against Antimicrobial Peptides in Staphylococcus aureus Alters Pharmacodynamics Beyond the MIC
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DOI：
10.3389/fmicb.2020.00103
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发表时间：
2020-02-14
影响因子：
5.2
通讯作者：
Rolff, Jens
中科院分区：
文献类型：
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作者：
El Shazely, Baydaa;Yu, Guozhi;Rolff, Jens
抗菌肽（Antimicrobial peptides，AMP）是一类很有前途的新型抗菌剂，其部分原因是抗菌肽不易产生耐药性。这可能是由于它们的作用方式，也可能是由于它们的药效学特征，这与常规抗生素有显著差异。虽然已经研究了抗生素耐药菌株的药效学，但缺乏AMP耐药菌株的此类数据。在这里，我们调查了革兰氏阳性的人类病原体金黄色葡萄球菌的药效学抗菌肽的选择下演变。有趣的是，希尔系数（kappa kappa）与最小抑制浓度（MIC）一起发展。除了一种基因型，即在menF和atl中携带突变的菌株外，所有突变体都具有比非选择的敏感对照更高的kappa。更高的kappa导致更陡峭的药效学曲线，重要的是，导致更窄的突变体选择窗口。S.选择对蜂毒肽具有抗性的金黄色葡萄球菌显示出对Pexiganan的交叉抗性，并且具有与Pexiganan选择的品系一样陡峭的药效学曲线（高Kappa）。相比之下，pexiganan敏感的tenecin选择的系显示出较低的kappa。总之，我们的数据表明，药效学参数不是特定药物/菌株相互作用的固定特征，而是在药物治疗下实际上发生变化。Kappa、最大和最小生长速率等因子对抗性进化的动态和概率的贡献是需要迫切关注的开放性问题。
Antimicrobial peptides (AMPs) have been proposed as a promising class of new antimicrobials partly because they are less susceptible to bacterial resistance evolution. This is possibly caused by their mode of action but also by their pharmacodynamic characteristics, which differ significantly from conventional antibiotics. Although pharmacodynamics of antibiotic resistant strains have been studied, such data are lacking for AMP resistant strains. Here, we investigated if the pharmacodynamics of the Gram-positive human pathogen Staphylococcous aureus evolve under antimicrobial peptide selection. Interestingly, the Hill coefficient (kappa kappa) evolves together with the minimum inhibition concentration (MIC). Except for one genotype, strains harboring mutations in menF and atl, all mutants had higher kappa than the non-selected sensitive controls. Higher kappa results in steeper pharmacodynamic curve and, importantly, in a narrower mutant selection window. S. aureus selected for resistance to melittin displayed cross resistant against pexiganan and had as steep pharmacodynamic curves (high kappa) as pexiganan-selected lines. By contrast, the pexiganan-sensitive tenecin-selected lines displayed lower kappa. Taken together, our data demonstrate that pharmacodynamic parameters are not fixed traits of particular drug/strain interactions but actually evolve under drug treatment. The contribution of factors such as kappa and the maximum and minimum growth rates on the dynamics and probability of resistance evolution are open questions that require urgent attention.