Infection and Drug Resistance (Nov 2023)
Combination of AS101 and Mefloquine Inhibits Carbapenem-Resistant Pseudomonas aeruginosa in vitro and in vivo
Abstract
Rongrong Li,1,2 Xuhang Shen,3 Zhengyuan Li,4 Jilong Shen,2 Hao Tang,5 Huaming Xu,6 Jilu Shen,1,7 Yuanhong Xu1 1Department of Clinical Laboratory, The First Affiliated Hospital of Anhui Medical University, Hefei, People’s Republic of China; 2Provincial Laboratories of Pathogen Biology and Zoonoses, Anhui Medical University, Hefei, People’s Republic of China; 3Department of Gastroenterology, The First Affiliated Hospital of Anhui Medical University, Hefei, People’s Republic of China; 4Orthopedics, The First Affiliated Hospital of Anhui Medical University, Hefei, People’s Republic of China; 5Department of Clinical Laboratory, the Second Affiliated Hospital of Anhui Medical University, Hefei, People’s Republic of China; 6Department of Clinical Laboratory, the First Affiliated Hospital of Anhui University of Traditional Chinese Medicine, Hefei, People’s Republic of China; 7Anhui Public Health Clinical Center, Hefei, People’s Republic of ChinaCorrespondence: Yuanhong Xu, Tel +86 13505694447, Email [email protected]: In recent years, carbapenem-resistant Pseudomonas aeruginosa (CRPA) has spread around the world, leading to a high mortality and close attention of medical community. In this study, we aim to find a new strategy of treatment for CRPA infections.Methods: Eight strains of CRPA were collected, and PCR detected the multi-locus sequence typing (MLST). The antimicrobial susceptibility test was conducted using the VITEK@2 compact system. The minimum inhibitory concentration (MIC) for AS101 and mefloquine was determined using the broth dilution method. Antibacterial activity was tested in vitro and in vivo through the chessboard assay, time killing assay, and a mouse model. The mechanism of AS101 combined with mefloquine against CRPA was assessed through the biofilm formation inhibition assay, electron microscopy, and detection of reactive oxygen species (ROS).Results: The results demonstrated that all tested CRPA strains exhibited multidrug resistance. Moreover, our investigation revealed a substantial synergistic antibacterial effect of AS101-mefloquine in vitro. The assay for inhibiting biofilm formation indicated that AS101-mefloquine effectively suppressed the biofilm formation of CRPA-5 and CRPA-6. Furthermore, AS101-mefloquine were observed to disrupt the bacterial cell wall and enhance the permeability of the cell membrane. This effect was achieved by stimulating the production of ROS, which in turn hindered the growth of CRPA-3. To evaluate the therapeutic potential, a murine model of CRPA-3 peritoneal infection was established. Notably, AS101-mefloquine administration resulted in a significant reduction in bacterial load within the liver, kidney, and spleen of mice after 72 hours of treatment.Conclusion: The present study showed that the combination of AS101 and mefloquine yielded a notable synergistic bacteriostatic effect both in vitro and in vivo, suggesting a potential clinical application of this combination in the treatment of CRPA.Keywords: AS101, mefloquine, carbapenem resistance, Pseudomonas aeruginosa, synergy, biofilm
