Institute of Microbiology & Infection, College of Medical and Dental Sciences, University of Birmingham, Birmingham B152TT, UK.
The Quadram Institute, Norwich Research Park, Norwich NR47UH, UK.
J Antimicrob Chemother. 2017 Oct 1;72(10):2755-2763. doi: 10.1093/jac/dkx201.
Cross-resistance between antibiotics and biocides is a potentially important driver of MDR. A relationship between susceptibility of Salmonella to quinolones and triclosan has been observed. This study aimed to: (i) investigate the mechanism underpinning this; (ii) determine whether the phenotype is conserved in Escherichia coli; and (iii) evaluate the potential for triclosan to select for quinolone resistance.
WT E. coli, Salmonella enterica serovar Typhimurium and gyrA mutants were used. These were characterized by determining antimicrobial susceptibility, DNA gyrase activity and sensitivity to inhibition. Expression of stress response pathways (SOS, RpoS, RpoN and RpoH) was measured, as was the fitness of mutants. The potential for triclosan to select for quinolone resistance was determined.
All gyrase mutants showed increased triclosan MICs and altered supercoiling activity. There was no evidence for direct interaction between triclosan and gyrase. Identical substitutions in GyrA had different impacts on supercoiling in the two species. For both, there was a correlation between altered supercoiling and expression of stress responses. This was more marked in E. coli, where an Asp87Gly GyrA mutant demonstrated greatly increased fitness in the presence of triclosan. Exposure of parental strains to low concentrations of triclosan did not select for quinolone resistance.
Our data suggest gyrA mutants are less susceptible to triclosan due to up-regulation of stress responses. The impact of gyrA mutation differs between E. coli and Salmonella. The impacts of gyrA mutation beyond quinolone resistance have implications for the fitness and selection of gyrA mutants in the presence of non-quinolone antimicrobials.
抗生素和消毒剂之间的交叉耐药性是导致 MDR 的一个潜在重要驱动因素。已经观察到沙门氏菌对喹诺酮类药物和三氯生的敏感性之间存在关系。本研究旨在：（i）研究其潜在机制；（ii）确定该表型在大肠杆菌中是否保守；以及（iii）评估三氯生选择喹诺酮类耐药的潜力。
使用了 WT 大肠杆菌、鼠伤寒沙门氏菌和 gyrA 突变体。通过测定抗菌药物敏感性、DNA 拓扑异构酶活性和抑制敏感性来对其进行特征描述。测量了应激反应途径（SOS、RpoS、RpoN 和 RpoH）的表达以及突变体的适应性。还确定了三氯生选择喹诺酮类耐药的潜力。
所有拓扑异构酶突变体的三氯生 MIC 均增加，超螺旋活性改变。没有证据表明三氯生与拓扑异构酶之间存在直接相互作用。在两种细菌中，GyrA 中的相同取代对超螺旋化的影响不同。对于两种细菌，超螺旋化改变与应激反应的表达之间均存在相关性。在大肠杆菌中更为明显，在三氯生存在的情况下，Asp87Gly GyrA 突变体表现出明显更高的适应性。亲本菌株暴露于低浓度的三氯生中不会选择出对喹诺酮类药物的耐药性。
我们的数据表明，由于应激反应的上调，gyrA 突变体对三氯生的敏感性降低。gyrA 突变在大肠杆菌和沙门氏菌中的影响不同。gyrA 突变除了对抗喹诺酮类药物的耐药性之外，还会对非喹诺酮类抗菌药物存在时 gyrA 突变体的适应性和选择产生影响。
