College of Veterinary Medicine, Henan Agricultural University, Zhengzhou, China.
Zhengzhou Animal Husbandry Bureau, Zhengzhou, China.
Microbiol Spectr. 2023 Aug 17;11(4):e0053023. doi: 10.1128/spectrum.00530-23. Epub 2023 Jun 26.
With the increasing and inappropriate use of colistin, the emerging colistin-resistant isolates have been frequently reported during the last few decades. Therefore, new potential targets and adjuvants to reverse colistin resistance are urgently needed. Our previous study has confirmed a marked increase of colistin susceptibility (16-fold compared to the wild-type Salmonella strain) of overexpression strain JSΔΔ::/p (simplified as JSΔΔ/p). To searching for potential new drug targets, the transcriptome and metabolome analysis were carried out in this study. We found that the more susceptible strain JSΔΔ/p displayed striking perturbations at both the transcriptomics and metabolomics levels. The virulence-related genes and colistin resistance-related genes (CRRGs) were significantly downregulated in JSΔΔ/p. There were significant accumulation of citrate, α-ketoglutaric acid, and agmatine sulfate in JSΔΔ/p, and exogenous supplement of them could synergistically enhance the bactericidal effect of colistin, indicating that these metabolites may serve as potential adjuvants for colistin therapy. Additionally, we also demonstrated that AcrB and CpxR could target the ATP and reactive oxygen species (ROS) generation, but not proton motive force (PMF) production pathway to potentiate antibacterial activity of colistin. Collectively, these findings have revealed several previously unknown mechanisms contributing to increased colistin susceptibility and identified potential targets and adjuvants for potentiating colistin treatment of Salmonella infections. Emergence of multidrug-resistant (MDR) Gram-negative (G) bacteria have led to the reconsideration of colistin as the last-resort therapeutic option for health care-associated infections. Finding new drug targets and strategies against the spread of MDR G bacteria are global challenges for the life sciences community and public health. In this paper, we demonstrated the more susceptibility strain JSΔΔ/p displayed striking perturbations at both the transcriptomics and metabolomics levels and revealed several previously unknown regulatory mechanisms of AcrB and CpxR on the colistin susceptibility. Importantly, we found that exogenous supplement of citrate, α-ketoglutaric acid, and agmatine sulfate could synergistically enhance the bactericidal effect of colistin, indicating that these metabolites may serve as potential adjuvants for colistin therapy. These results provide a theoretical basis for finding potential new drug targets and adjuvants.
随着多粘菌素的不合理使用不断增加，在过去几十年中，经常有新的多粘菌素耐药分离株出现。因此，迫切需要新的潜在靶点和佐剂来逆转多粘菌素耐药性。我们之前的研究已经证实，过度表达菌株 JSΔΔ::/p（简化为 JSΔΔ/p）使多粘菌素的敏感性显著增加（与野生型沙门氏菌菌株相比增加了 16 倍）。为了寻找潜在的新药靶标，本研究进行了转录组和代谢组分析。我们发现，更敏感的菌株 JSΔΔ/p 在转录组和代谢组水平上都显示出明显的干扰。JSΔΔ/p 中的毒力相关基因和多粘菌素耐药相关基因（CRRGs）显著下调。JSΔΔ/p 中柠檬酸、α-酮戊二酸和硫酸胍丁胺显著积累，外源补充这些物质可协同增强多粘菌素的杀菌作用，表明这些代谢物可能作为多粘菌素治疗的潜在佐剂。此外，我们还证明了 AcrB 和 CpxR 可以靶向 ATP 和活性氧（ROS）的产生，而不是质子动力（PMF）产生途径来增强多粘菌素的抗菌活性。总的来说，这些发现揭示了几种以前未知的机制，这些机制有助于增加多粘菌素的敏感性，并确定了增强多粘菌素治疗沙门氏菌感染的潜在靶点和佐剂。多药耐药（MDR）革兰氏阴性（G）细菌的出现使得多粘菌素再次被视为治疗与保健相关感染的最后手段。寻找针对 MDR G 细菌传播的新药物靶点和策略是生命科学领域和公共卫生领域的全球性挑战。在本文中，我们证明了更敏感的菌株 JSΔΔ/p 在转录组和代谢组水平上都显示出明显的干扰，并揭示了 AcrB 和 CpxR 对多粘菌素敏感性的几个以前未知的调节机制。重要的是，我们发现外源补充柠檬酸、α-酮戊二酸和硫酸胍丁胺可以协同增强多粘菌素的杀菌作用，表明这些代谢物可能作为多粘菌素治疗的潜在佐剂。这些结果为寻找潜在的新药靶标和佐剂提供了理论依据。
