University of Würzburg, Institute of Pharmacy and Food Chemistry, Würzburg, Germany.
University of Würzburg, Institute for Molecular Infection Biology, Würzburg, Germany.
Antimicrob Agents Chemother. 2018 Jan 25;62(2). doi: 10.1128/AAC.01510-17. Print 2018 Feb.
Recently, the nitro-substituted bisquaternary bisnaphthalimides were reported to have substantial anti-infective activity against Gram-positive bacteria, including methicillin-resistant (MRSA). Here, we selected resistant clones by cultivation in increasing concentrations of the most active compound, MT02. Interestingly, MT02-resistant variants induced a diffusible red color of the broth. Chromatographic and spectroscopic investigations revealed a stepwise reduction of the bisquaternary bisnaphthalimides' nitro groups to amino groups. The corresponding derivatives were completely inactive against staphylococci. RNA sequencing experiments revealed a strong overexpression of a novel oxidoreductase in MT02-resistant strains. Deletion mutants of this enzyme did not produce the red color and were not able to develop resistance against bisquaternary bisnaphthalimides. Biochemical reactions confirmed an NADH-dependent deactivation of the nitro-substituted compounds. Thus, this is the first report of a nitroreductase-based antibiotic resistance mechanism in the human pathogen .
最近，报道称硝基取代的双季铵双萘酰亚胺对革兰氏阳性菌（包括耐甲氧西林金黄色葡萄球菌[MRSA]）具有显著的抗感染活性。在这里，我们通过在浓度逐渐增加的最有效化合物 MT02 中培养来选择耐药克隆。有趣的是，MT02 耐药变体诱导肉汤产生可扩散的红色。色谱和光谱研究表明，双季铵双萘酰亚胺的硝基基团逐步还原为氨基基团。相应的衍生物对葡萄球菌完全没有活性。RNA 测序实验表明，MT02 耐药菌株中一种新型氧化还原酶的表达水平强烈上调。该酶的缺失突变体不会产生红色，并且无法对双季铵双萘酰亚胺产生耐药性。生化反应证实了 NADH 依赖性硝基取代化合物的失活。因此，这是人类病原体中基于硝基还原酶的抗生素耐药机制的首次报道。
