Extreme Acid Modulates Fitness Trade-Offs of Multidrug Efflux Pumps MdtEF-TolC and AcrAB-TolC in Escherichia coli K-12
Extreme Acid Modulates Fitness Trade-Offs of Multidrug Efflux Pumps MdtEF-TolC and AcrAB-TolC in Escherichia coli K-12
复制标题
极端酸调节大肠杆菌 K-12 中多药外排泵 MdtEF-TolC 和 AcrAB-TolC 的适应性权衡
DOI：
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发表时间：
2021
影响因子：
4.4
通讯作者：
J. Slonczewski
中科院分区：
文献类型：
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作者：
Samantha H. Schaffner;Abigail V. Lee;M. Pham;Beimnet B. Kassaye;Haofan Li;Sheetal Tallada;Cassandra Lis;Mark Lang;Yangyang Liu;Nafeez Ahmed;Logan G. Galbraith;Jeremy Moore;Katarina M. Bischof;Chelsea C. Menke;J. Slonczewski
到达肠道的抗生素和其他药物必须通过胃酸。然而，人们对极端酸如何调节药物对肠道细菌的影响知之甚少。摘要 细菌基因组编码各种多药外排泵（MDR），其适应优势的具体条件尚不清楚。我们证明，大肠杆菌中的外排泵 MdtEF-TolC 在暴露于极端酸（pH 2）时具有适应性优势。我们的流式细胞术方法揭示了胆汁酸（主要泵底物）和水杨酸之间的 pH 依赖性适应性权衡，水杨酸是一种膜渗透芳香酸，可诱导耐药调节子但会消耗质子动力 (PMF)。 PMF 驱动 MdtEF-TolC 和相关泵，例如 AcrAB-TolC。 mdtE 的缺失（泵 MdtEF-TolC 的丢失）增加了菌株在有或没有水杨酸盐或胆汁酸的情况下生长过程中的相对适应性。然而，当生长周期包括在 pH 2（低于 pH 生长范围）下孵育 2 小时时，MdtEF-TolC 具有适应性优势。健康优势需要胆汁盐，但由于水杨酸盐的存在而降低，而水杨酸盐的吸收会被酸放大。相比之下，AcrAB-TolC（胆汁酸的主要外排泵）在生长周期中无论是否暴露于酸，都具有 PMF 依赖性的适应性优势。另一种 MDR 泵 EmrAB-TolC 在胆汁酸存在的情况下在生长过程中没有提供选择性益处。如果没有胆汁酸，所有三种 MDR 泵在暴露于 pH 2 时都会因水杨酸盐而产生巨大的适应性成本。这些结果与低 pH 下水杨酸盐的吸收增加一致。总体而言，我们表明 MdtEF-TolC 是一种适合短暂极端酸暴露的 MDR 泵，并且低 pH 值会放大药物泵的水杨酸盐依赖性适应性成本。重要性 到达肠道的抗生素和其他药物必须通过胃酸。然而，人们对极端酸如何调节药物对肠道细菌的影响知之甚少。我们发现，接触极端酸性物质会给多药泵带来健康优势，否则会产生健康成本。同时，极端酸放大了水杨酸盐选择对多药泵的影响。因此，有机酸和胃酸在调节肠道微生物组的多药耐药性中发挥重要作用。我们的流式细胞术分析提供了一种方法来测量极端酸暴露于各种膜溶性有机酸（包括植物源性营养素和药剂）的适应性影响。可以设计治疗酸来控制环境和宿主相关栖息地中多药泵的流行。
Antibiotics and other drugs that reach the gut must pass through stomach acid. However, little is known of how extreme acid modulates the effect of drugs on gut bacteria. ABSTRACT Bacterial genomes encode various multidrug efflux pumps (MDR) whose specific conditions for fitness advantage are unknown. We show that the efflux pump MdtEF-TolC, in Escherichia coli, confers a fitness advantage during exposure to extreme acid (pH 2). Our flow cytometry method revealed pH-dependent fitness trade-offs between bile acids (a major pump substrate) and salicylic acid, a membrane-permeant aromatic acid that induces a drug resistance regulon but depletes proton motive force (PMF). The PMF drives MdtEF-TolC and related pumps such as AcrAB-TolC. Deletion of mdtE (with loss of the pump MdtEF-TolC) increased the strain’s relative fitness during growth with or without salicylate or bile acids. However, when the growth cycle included a 2-h incubation at pH 2 (below the pH growth range), MdtEF-TolC conferred a fitness advantage. The fitness advantage required bile salts but was decreased by the presence of salicylate, whose uptake is amplified by acid. For comparison, AcrAB-TolC, the primary efflux pump for bile acids, conferred a PMF-dependent fitness advantage with or without acid exposure in the growth cycle. A different MDR pump, EmrAB-TolC, conferred no selective benefit during growth in the presence of bile acids. Without bile acids, all three MDR pumps incurred a large fitness cost with salicylate when exposed at pH 2. These results are consistent with the increased uptake of salicylate at low pH. Overall, we showed that MdtEF-TolC is an MDR pump adapted for transient extreme-acid exposure and that low pH amplifies the salicylate-dependent fitness cost for drug pumps. IMPORTANCE Antibiotics and other drugs that reach the gut must pass through stomach acid. However, little is known of how extreme acid modulates the effect of drugs on gut bacteria. We find that extreme-acid exposure leads to a fitness advantage for a multidrug pump that otherwise incurs a fitness cost. At the same time, extreme acid amplifies the effect of salicylate selection against multidrug pumps. Thus, organic acids and stomach acid could play important roles in regulating multidrug resistance in the gut microbiome. Our flow cytometry assay provides a way to measure the fitness effects of extreme-acid exposure to various membrane-soluble organic acids, including plant-derived nutrients and pharmaceutical agents. Therapeutic acids might be devised to control the prevalence of multidrug pumps in environmental and host-associated habitats.
DOI：
10.1152/ajpgi.00027.2007
发表时间：
2007-07-01
影响因子：
4.5
作者：
Hamilton, James P.;Xie, Guofeng;Hofmann, Alan F.
通讯作者：
Hofmann, Alan F.