Investigating the role of the uncharacterized gene ygfB in the resistance of multidrug resistant Pseudomonas aeruginosa to β-lactam antibiotics

研究未表征基因 ygfB 在多重耐药铜绿假单胞菌对 β-内酰胺抗生素耐药性中的作用

• 批准号: 451686679
• 负责人: Dr. Erwin Bohn
• 金额: --
• 依托单位: Institut für Medizinische Mikrobiologie und Hygiene
• 依托单位国家: 德国
• 项目类别: Research Grants
• 资助国家: 德国
• 项目状态: 未结题
• 来源: https://gepris.dfg.de/gepris/projekt/451686679?language=en
• 关键词: Investigating; role; uncharacterized; gene; ygfB

The hyperproduction of the ß-lactamase AmpC is an important cause of resistance to ß-lactams in Pseudomonas aeruginosa (Pa). While Pa ampC expression is known to depend on the transcriptional activator AmpR, the signals that enable AmpC hyperproduction remain elusive. A better understanding of such factors could help develop novel therapeutic strategies against multidrug resistant Pa strains, which are becoming increasingly prevalent in health care settings.AmpC hyperproduction is most frequently caused by inactivation of the genes dacB and ampD, which encode for the penicillin-binding protein PBP4 and the peptidoglycan-recycling amidase AmpD, respectively. The key events leading to ß-lactam resistance as a result of PBP4 inactivation seem to be (i) a high production of anhydro-MurNac-pentapeptides, which effectively derepress AmpR, and (ii) the activation of the two component system CreBC. How activation of CreBC contributes to ß-lactam resistance is unclear.In a recent study we identified the genes that contribute the most to ß-lactam resistance in the AmpC hyper-producing Pa clinical isolate ID40, a strain which carries a loss of function mutation in dacB. One of the genes we found to be crucial for full ß-lactam resistance is the uncharacterized gene ygfB. Preliminary studies suggest that YgfB transcriptionally represses the ampD paralogue encoding for the amidase AmpDh3 in ID40. Deletion of ygfB upregulates ampDh3 expression, which, in turn, leads to decreased ampC expression. These data suggest that the transcriptional repression of ampDh3 is critical to ensure high AmpC levels in a dacB mutant. In the proposed study, we want to elucidate in detail how YgfB contributes to antibiotic resistance in Pa.

AmpC酶的高产是铜绿假单胞菌对β-内酰胺类抗生素耐药的重要原因。虽然已知PA AmpC的表达依赖于转录激活因子AMPR，但使AmpC过度产生的信号仍然难以捉摸。对这些因素的更好了解有助于开发针对多药耐药PA菌株的新治疗策略，这些菌株在医疗保健环境中正变得越来越普遍。AmpC的高产最常见的原因是编码青霉素结合蛋白PBP4和肽聚糖循环酰胺酶AmpD的基因dacB和ampD的失活。由于PBP4失活而导致内酰胺类抗生素抗性的关键事件似乎是(I)高产量的脱水-MurNac-五肽，它有效地降低了AMPR的表达，以及(Ii)双组分系统CreBC的激活。在最近的一项研究中，我们确定了高产AmpC的PA临床分离株ID40中导致β-内酰胺类耐药性最大的基因，ID40是一株在dacB中携带功能突变的菌株。我们发现的对内酰胺类抗生素完全耐药至关重要的基因之一是未鉴定的基因ygfB。初步研究表明，YgfB在转录上抑制了ID40中酰胺酶AmpDh3的ampD类似物的编码。YgfB的缺失上调了ampDh3的表达，进而导致ampC的表达下降。这些数据表明，ampDh3的转录抑制是确保dacB突变体中高AmpC水平的关键。在这项拟议的研究中，我们希望详细阐明YgfB是如何导致PA的抗生素耐药性的。