Mohiuddin Sayed Golam, Ngo Han, Orman Mehmet A
William Brookshire Chemical and Biomolecular Engineering Department, University of Houston, Houston, TX, USA.
NPJ Antimicrob Resist. 2024 Jun 24;2(1):17. doi: 10.1038/s44259-024-00034-7.
Metabolic inhibitors are known to exhibit complex interactions with antibiotics in bacteria, potentially acting as antagonists by inducing cell dormancy and promoting cell survival. However, the specific synergistic or antagonistic effects of these inhibitors depend on factors like their mechanisms of action, concentrations, and treatment timings, which require further investigation. In our study, we systematically explored the synergistic interactions of various metabolic inhibitors-such as chloramphenicol (a translation inhibitor), rifampicin (a transcription inhibitor), arsenate (an ATP production inhibitor), and thioridazine (a PMF inhibitor)-in combination with ofloxacin. We conducted this investigation under pre-, co-, and post-treatment conditions, employing a wide concentration range and utilizing four distinct synergy models. Chloramphenicol, rifampicin, and arsenate consistently showed minimal synergy scores, indicating a notable antagonistic relationship with ofloxacin across all models and conditions. In contrast, thioridazine consistently demonstrated elevated synergy scores, especially in pre- and co-treatment scenarios, albeit its synergy decreased during post-treatment conditions. When multivariable linear regression analyses were used for all drugs and conditions examined, a correlation between the synergy of thioridazine and its ability to suppress cellular energy metabolism became evident, underscoring the potential utility of certain metabolic inhibitors as effective anti-persistence adjuvants.
已知代谢抑制剂在细菌中与抗生素表现出复杂的相互作用，可能通过诱导细胞休眠和促进细胞存活而发挥拮抗剂作用。然而，这些抑制剂的具体协同或拮抗作用取决于其作用机制、浓度和处理时间等因素，这需要进一步研究。在我们的研究中，我们系统地探索了各种代谢抑制剂（如氯霉素（一种翻译抑制剂）、利福平（一种转录抑制剂）、砷酸盐（一种ATP产生抑制剂）和硫利达嗪（一种质子动力势抑制剂））与氧氟沙星联合使用时的协同相互作用。我们在预处理、共处理和后处理条件下进行了这项研究，采用了广泛的浓度范围，并使用了四种不同的协同模型。氯霉素、利福平和砷酸盐始终显示出最小的协同得分，表明在所有模型和条件下与氧氟沙星存在显著的拮抗关系。相比之下，硫利达嗪始终显示出较高的协同得分，特别是在预处理和共处理情况下，尽管其在处理后条件下的协同作用有所下降。当对所有检测的药物和条件进行多变量线性回归分析时，硫利达嗪的协同作用与其抑制细胞能量代谢的能力之间的相关性变得明显，这突出了某些代谢抑制剂作为有效抗持续感染佐剂的潜在效用。
