Lauxen Anna I, Kobauri Piermichele, Wegener Michael, Hansen Mickel J, Galenkamp Nicole S, Maglia Giovanni, Szymanski Wiktor, Feringa Ben L, Kuipers Oscar P
Department of Molecular Genetics, University of Groningen, Nijenborgh 7, 9747 AG Groningen, The Netherlands.
Stratingh Institute for Chemistry, University of Groningen, Nijenborgh 4, 9747 AG Groningen, The Netherlands.
Pharmaceuticals (Basel). 2021 Apr 21;14(5):392. doi: 10.3390/ph14050392.
During the last decades, a continuous rise of multi-drug resistant pathogens has threatened antibiotic efficacy. To tackle this key challenge, novel antimicrobial therapies are needed with increased specificity for the site of infection. Photopharmacology could enable such specificity by allowing for the control of antibiotic activity with light, as exemplified by /-tetra--chloroazobenzene-trimethoprim (TCAT) conjugates. Resistance development against the on (irradiated, TCATa) and off (thermally adapted, TCATd) states of TCAT were compared to that of trimethoprim (TMP) in mutant strain CS1562. Genomics and transcriptomics were used to explore the acquired resistance. Although TCAT shows TMP-like dihydrofolate reductase (DHFR) inhibition in vitro, transcriptome analyses show different responses in acquired resistance. Resistance against TCATa (on) relies on the production of exopolysaccharides and overexpression of TolC. While resistance against TCATd (off) follows a slightly different gene expression profile, both indicate hampering the entrance of the molecule into the cell. Conversely, resistance against TMP is based on alterations in cell metabolism towards a more persister-like phenotype, as well as alteration of expression levels of enzymes involved in the folate biosynthesis. This study provides a deeper understanding of the development of new therapeutic strategies and the consequences on resistance development against photopharmacological drugs.
在过去几十年中，多重耐药病原体的持续增加威胁着抗生素的疗效。为应对这一关键挑战，需要具有更高感染部位特异性的新型抗菌疗法。光药理学可以通过利用光来控制抗生素活性实现这种特异性，例如 /-四 - 氯偶氮苯 - 甲氧苄啶（TCAT）缀合物。在突变菌株CS1562中，将针对TCAT的开启（照射状态，TCATa）和关闭（热适应状态，TCATd）状态的耐药性发展与甲氧苄啶（TMP）的耐药性发展进行了比较。利用基因组学和转录组学来探索获得性耐药性。虽然TCAT在体外表现出类似TMP 的二氢叶酸还原酶（DHFR）抑制作用，但转录组分析显示在获得性耐药性方面有不同的反应。对TCATa（开启）的耐药性依赖于胞外多糖的产生和TolC的过表达。虽然对TCATd（关闭）的耐药性遵循略有不同的基因表达谱，但两者都表明阻碍了分子进入细胞。相反，对TMP的耐药性基于细胞代谢向更类似持留菌表型的改变，以及叶酸生物合成中涉及的酶表达水平的改变。这项研究为新治疗策略的开发以及对光药理学药物耐药性发展的后果提供了更深入的理解。
