Centre for BioSystems Science and Engineering, Indian Institute of Science, Bengaluru 560012, India.
Department of Biochemistry, Indian Institute of Science, Bengaluru 560012, India.
FEMS Microbiol Lett. 2018 Nov 1;365(22). doi: 10.1093/femsle/fny251.
The factors contributing to antibiotic resistance in bacteria are an important area of study. Sodium salicylate (NaSal), a non-steroidal anti-inflammatory drug (NSAID), increases antibiotic resistance by inducing the expression of MarA, a transcription factor, which increases the AcrAB-TolC efflux pump. MarA is a substrate of Lon protease and the Δlon strain displays a high degree of antibiotic resistance. This study was initiated to identify commonly used NSAIDs that may induce antibiotic resistance and to compare their efficacies with NaSal and acetyl salicylic acid (ASA). Quantitative real-time expression analysis revealed induction of marA and acrB by NaSal, ASA, acetaminophen (APAP) and ibuprofen. Further, dose studies demonstrated that NaSal and ASA induce resistance at ∼2 mM while APAP and ibuprofen induce resistance at ∼5-10 mM. To dissect the roles of key molecules, atomic force microscopy and functional studies were performed using WT, Δlon, ΔmarA, ΔacrB, ΔlonΔmarA and ΔlonΔacrB strains. The induction of antibiotic resistance by NaSal, ASA and APAP is relatively higher and is partly dependent on marA, whereas ibuprofen which induces lower antibiotic resistance shows complete marA dependence. Notably, NaSal, ASA, APAP and ibuprofen induce antibiotic resistance in an acrB-dependent manner. The possible significance of some NSAIDs in inducing antibiotic resistance is discussed.
导致细菌对抗生素产生抗药性的因素是一个重要的研究领域。水杨酸钠（NaSal）是一种非甾体抗炎药（NSAID），通过诱导转录因子 MarA 的表达来增加抗生素耐药性，MarA 是 Lon 蛋白酶的底物，而Δlon 菌株表现出高度的抗生素耐药性。本研究旨在确定可能诱导抗生素耐药性的常用 NSAIDs，并将其与 NaSal 和乙酰水杨酸（ASA）的疗效进行比较。定量实时表达分析显示 NaSal、ASA、对乙酰氨基酚（APAP）和布洛芬均可诱导 marA 和 acrB 的表达。此外，剂量研究表明，NaSal 和 ASA 在约 2mM 时诱导耐药，而 APAP 和布洛芬在约 5-10mM 时诱导耐药。为了剖析关键分子的作用，使用 WT、Δlon、ΔmarA、ΔacrB、ΔlonΔmarA 和 ΔlonΔacrB 菌株进行了原子力显微镜和功能研究。NaSal、ASA 和 APAP 诱导抗生素耐药性的相对较高，部分依赖于 marA，而诱导较低抗生素耐药性的布洛芬则完全依赖于 marA。值得注意的是，NaSal、ASA、APAP 和布洛芬以 acrB 依赖性方式诱导抗生素耐药性。讨论了一些 NSAIDs 诱导抗生素耐药性的可能意义。
