Institute for Medical Microbiology and Hygiene, Interfaculty Institute of Microbiology and Infection Medicine (IMIT), Eberhard Karls University Tübingen, Tübingen, Germany.
German Centre for Infection Research (DZIF), Partner Site Tübingen, Tübingen, Germany.
Commun Biol. 2023 Mar 10;6(1):254. doi: 10.1038/s42003-023-04609-4.
YgfB-mediated β-lactam resistance was recently identified in multi drug resistant Pseudomonas aeruginosa. We show that YgfB upregulates expression of the β-lactamase AmpC by repressing the function of the regulator of the programmed cell death pathway AlpA. In response to DNA damage, the antiterminator AlpA induces expression of the alpBCDE autolysis genes and of the peptidoglycan amidase AmpDh3. YgfB interacts with AlpA and represses the ampDh3 expression. Thus, YgfB indirectly prevents AmpDh3 from reducing the levels of cell wall-derived 1,6-anhydro-N-acetylmuramyl-peptides, required to induce the transcriptional activator AmpR in promoting the ampC expression and β-lactam resistance. Ciprofloxacin-mediated DNA damage induces AlpA-dependent production of AmpDh3 as previously shown, which should reduce β-lactam resistance. YgfB, however, counteracts the β-lactam enhancing activity of ciprofloxacin by repressing ampDh3 expression and lowering the benefits of this drug combination. Altogether, YgfB represents an additional player in the complex regulatory network of AmpC regulation.
YgfB 介导的β-内酰胺耐药性最近在多药耐药铜绿假单胞菌中被发现。我们表明，YgfB 通过抑制程序性细胞死亡途径 AlpA 的调节剂的功能来上调β-内酰胺酶 AmpC 的表达。响应于 DNA 损伤，反终止子 AlpA 诱导 alpBCDE 自溶基因和肽聚糖 amidase AmpDh3 的表达。YgfB 与 AlpA 相互作用并抑制 ampDh3 的表达。因此，YgfB 间接阻止 AmpDh3 降低细胞壁衍生的 1,6-脱水-N-乙酰基muramyl-肽的水平，这对于诱导转录激活物 AmpR 促进 ampC 表达和β-内酰胺耐药性是必需的。正如先前所示，环丙沙星介导的 DNA 损伤诱导 AlpA 依赖性 AmpDh3 的产生，这应该降低β-内酰胺耐药性。然而，YgfB 通过抑制 ampDh3 的表达并降低这种药物组合的益处，抵消了环丙沙星的β-内酰胺增强活性。总之，YgfB 代表 AmpC 调节复杂调控网络中的另一个参与者。
