Upmanyu Kirti, Rizwanul Haq Qazi Mohd, Singh Ruchi
ICMR-National Institute of Pathology, Safdarjung Hospital Campus, New Delhi 110029, India.
Department of Biosciences, Jamia Millia Islamia, A Central University, New Delhi 110025, India.
Antibiotics (Basel). 2023 Jul 6;12(7):1155. doi: 10.3390/antibiotics12071155.
Antibiotic-resistant infections among patients in hospital settings are rising at an alarming rate. The World Health Organization has designated carbapenem-resistant as a priority pathogen for drug discovery. Based on the open drug discovery approach, we screened 400 compounds provided as a Pandemic Response Box by MMV and DNDi to identify compounds with antibacterial and antibiofilm activity against two reference strains using a highly robust resazurin assay. In vitro screening identified thirty compounds with MIC ≤ 50μM having growth inhibitory properties against the planktonic state. Five compounds, with MMV IDs MMV396785, MMV1578568, MMV1578574, MMV1578564, and MMV1579850, were able to reduce metabolically active cells in the biofilm state. Of these five compounds, MMV396785 showed potential antibacterial and antibiofilm activity with MIC, MBIC, and MBEC of 3.125 μM, 12.5, and 25-100 µM against tested strains, respectively, showing biofilm formation inhibition by 93% and eradication of pre-formed biofilms by 60-77.4%. In addition, MMV396785 showed a drastic reduction in the surface area and thickness of biofilms. Further investigations at the molecular level by qRT-PCR revealed the downregulation of biofilm-associated genes when exposed to 50 µM MMV396785 in all tested strains. This study identified the novel compound MMV396785 as showing potential in vitro antibacterial and antibiofilm efficacy against .
医院环境中患者的抗生素耐药性感染正以惊人的速度上升。世界卫生组织已将耐碳青霉烯类细菌指定为药物研发的优先病原体。基于开放药物研发方法，我们筛选了由MMV和DNDi作为大流行应对药盒提供的400种化合物，以使用高度可靠的刃天青测定法鉴定对两种参考菌株具有抗菌和抗生物膜活性的化合物。体外筛选鉴定出30种MIC≤50μM的化合物，它们对浮游状态具有生长抑制特性。五种化合物，其MMV编号分别为MMV396785、MMV1578568、MMV1578574、MMV1578564和MMV1579850，能够减少生物膜状态下的代谢活性细胞。在这五种化合物中，MMV396785对测试菌株显示出潜在的抗菌和抗生物膜活性，其MIC、MBIC和MBEC分别为3.125μM、12.5μM和25 - 100μM，生物膜形成抑制率为93%，对预先形成的生物膜的根除率为60 - 77.4%。此外，MMV396785使生物膜的表面积和厚度大幅减少。通过qRT-PCR在分子水平上的进一步研究表明，在所有测试菌株中，当暴露于50μM的MMV396785时，生物膜相关基因下调。本研究确定新型化合物MMV396785在体外对……显示出潜在的抗菌和抗生物膜功效。
