Department of Infectious Diseases and the Key Lab of Endogenous Infection, Shenzhen Nanshan People's Hospital and the 6th Affiliated Hospital of Shenzhen University Health Science Center, Shenzhen, Guangdong 518052, China.
Department of Environmental Health Sciences, School of Public Health, University of Michigan, Ann Arbor, Michigan 48109, United States.
ACS Infect Dis. 2021 Jun 11;7(6):1690-1701. doi: 10.1021/acsinfecdis.1c00030. Epub 2021 May 21.
Biofilm formation and hemolysis induced by are closely related to pathogenicity. However, no drugs exist to inhibit biofilm formation or hemolysis induced by in clinical practice. This study found diclazuril had antibacterial action against with minimum inhibitory concentrations (MICs) at 50 μM for both methicillin-sensitive (MSSA) and methicillin-resistant (MRSA). Diclazuril (at 1/4× or 1/8× MICs) significantly inhibited biofilm formation of under static or flow-based conditions and also inhibited hemolysis induced by . The RNA levels of transcriptional regulatory genes (, , , , , , ), biofilm formation-related genes (, , , , , , , , , , ), and virulence-related genes (, , , , , , , , , , ) of were decreased when treated by diclazuril (at 1/4× MIC) for 4 h. The diclazuril nonsensitive clones of were selected by induction of wildtype strains for about 90 days under the pressure of diclazuril. Mutations in the possible target genes of diclazuril against were detected by whole-genome sequencing. This study indicated that there were three amino acid mutations in the diclazuril nonsensitive clone of , two of which were located in genes with known function (SMC-Scp complex subunit ScpB and glyceraldehyde-3-phosphate dehydrogenase 1, respectively) and one in a gene with unknown function (hypothetical protein). Diclazuril showed a strong inhibition effect on planktonic cells and biofilm formation of with the overexpression of the gene.
生物膜形成和溶血由 引起，与致病性密切相关。然而，在临床实践中，没有药物可以抑制 引起的生物膜形成或溶血。本研究发现地克珠利对 具有抗菌作用，甲氧西林敏感金黄色葡萄球菌（MSSA）和甲氧西林耐药金黄色葡萄球菌（MRSA）的最低抑菌浓度（MIC）均为 50 μM。地克珠利（1/4×或 1/8×MIC）显著抑制 静态或流动条件下的生物膜形成，也抑制 引起的溶血。用地克珠利（1/4×MIC）处理 4 h 后， 转录调控基因（ 、 、 、 、 、 ）、生物膜形成相关基因（ 、 、 、 、 、 、 、 ）和毒力相关基因（ 、 、 、 、 、 、 、 ）的 RNA 水平降低。通过在 地克珠利压力下诱导野生型菌株约 90 天，选择 地克珠利不敏感克隆。通过全基因组测序检测到 对地克珠利可能的靶基因的突变。本研究表明， 地克珠利不敏感克隆中有三个氨基酸突变，其中两个位于具有已知功能的基因（SMC-Scp 复合物亚基 ScpB 和甘油醛-3-磷酸脱氢酶 1）中，一个位于具有未知功能的基因（假定蛋白）中。地克珠利对地克珠利过表达的浮游细胞和 生物膜形成具有很强的抑制作用。
