Department of Biotechnology, Panjab University, BMS Block-I, Sector- 25, Chandigarh, 160014, India.
Department of Microbiology, Panjab University, BMS Block-I, Sector- 25, Chandigarh, 160014, India.
Microbiol Res. 2021 Jan;242:126627. doi: 10.1016/j.micres.2020.126627. Epub 2020 Oct 20.
Acinetobacter baumannii is clinically one of the most significant pathogens, especially in intensive care settings, because of its multidrug-resistance (MDR). Repurposing of high-affinity drugs is a faster and more plausible approach for combating the emergence of MDR and to tackle bacterial infections. This study was aimed to evaluate the approved drugs potentially inhibiting A. baumannii PPK1 (AbPPK1) mediated synthesis of polyphosphates (polyP). Based on virtual screening, molecular dynamic simulation, and CD spectroscopy for thermal stability, two stable ligands, etoposide and genistein, were found with promising contours for further investigation. Following in vitro inhibition of AbPPK1, the efficacy of selected drugs was further tested against virulence traits of A. baumannii. These drugs significantly reduced the biofilm formation, surface motility in A. baumannii and led to decreased survival under desiccation. In addition to inhibition of PPK1, both drugs increased the expression of polyP degrading enzyme, exopolyphosphatase (PPX), that might be responsible for the decrease in the total cellular polyP. Since polyP modulates the virulence factors in bacteria, destabilization of the polyP pool by these drugs seems particularly striking for their therapeutic applications against A. baumannii.
鲍曼不动杆菌是临床上最重要的病原体之一，尤其是在重症监护环境中，因为它具有多重耐药性（MDR）。重新利用高亲和力的药物是对抗 MDR 出现和解决细菌感染的更快、更合理的方法。本研究旨在评估可能抑制鲍曼不动杆菌 PPK1（AbPPK1）介导的多磷酸盐（polyP）合成的已批准药物。基于虚拟筛选、分子动力学模拟和 CD 光谱对热稳定性的研究，发现了两种稳定的配体依托泊苷和染料木黄酮，它们具有进一步研究的有希望的轮廓。在体外抑制 AbPPK1 后，进一步测试了选定药物对鲍曼不动杆菌毒力特征的疗效。这些药物显著减少了鲍曼不动杆菌的生物膜形成和表面运动，并导致在干燥条件下的存活率降低。除了抑制 PPK1 外，这两种药物还增加了多磷酸盐降解酶外多磷酸盐酶（PPX）的表达，这可能是导致细胞内总多磷酸盐减少的原因。由于多磷酸盐调节细菌中的毒力因子，这些药物对多磷酸盐池的不稳定性对其治疗鲍曼不动杆菌的应用似乎特别引人注目。
