NMPA-approved traditional Chinese medicine-Pingwei Pill: new indication for colistin recovery against MCR-positive bacteria infection

Abstract

Background The wide spread of plasmid-mediated colistin resistance by mobile colistin resistance (MCR) in Enterobacteriaceae severely limits the clinical application of colistin as a last-line drug against bacterial infection. The identification of colistin potentiator from natural plants or their compound preparation as antibiotic adjuncts is a new promising strategy to meet this challenge. Methods Herein, the synergistic activity, as well as the potential mechanism, of Pingwei pill plus antibiotics against MCR-positive Gram-negative pathogens was examined using checkerboard assay, time-killing curves, combined disk test, western blot assay, and microscope analysis. Additionally, the Salmonella sp. HYM2 infection models of mouse and chick were employed to examine the in vivo efficacy of Pingwei pill in combination with colistin against bacteria infection. Finally, network pharmacology and molecular docking assay were used to predicate other actions of Pingwei pill for Salmonella infection. Results Our results revealed that Pingwei Pill synergistically potentiated the antibacterial activity of colistin against MCR-1-positive bacteria by accelerating the damage and permeability of the bacterial outer membrane with an FIC (Fractional Inhibitory Concentration) index less than 0.5. The treatment of Pingwei Pill neither inhibited bacterial growth nor affected MCR production. Notably, Pingwei Pill in combination with colistin significantly prolonged the median survival in mouse and chick models of infection using the Salmonella sp. strain HYM2, decreased bacteria burden and organ index of infected animal, alleviated pathological damage of cecum, which suggest that Pingwei Pill recovered the therapeutic performance of colistin for MCR-1- positive Salmonella infection in mice and the naturally infected host chick. Pharmacological network topological analysis, molecular docking, bacterial adhesion, and invasion pathway verification assays were performed to identify the other molecular mechanisms of Pingwei Pill as a colistin potentiator against Gram-negative bacteria infection. Conclusion Taken together, NMPA (National Medical Products Administration)-approved Pingwei Pill is a promising adjuvant with colistin for MCR-positive bacterial infection with a shortened R&D (research and development) cycle and affordable R&D cost and risk.

Naringenin Microsphere as a Novel Adjuvant Reverses Colistin Resistance via Various Strategies against Multidrug-Resistant Klebsiella pneumoniae Infection

“…Naringenin Was an Effective Adjunct to Reverse Colistin Resistance. As a multidrug-resistant stain, 35 K. pneumoniae ZJ02 was used in the identification of potential candidates as a colistin adjunct by the chessboard assay. As expected, naringenin (Figure S1A) was gathered from foodborne compounds displaying prominent synergy with colistin (Figure S1B) against K. pneumoniae ZJ02.…”

Multi-component Chinese medicine formulas for drug discovery: State of the art and future perspectives

“…After the intersection of drug targets and disease targets, a "drug-intersection target gene-disease" network is constructed. The interactions between drugs and diseases are explored through visualization tools and algorithms to reveal the potential mechanisms of drug treatments for diseases [81,82].…”

Phosphoethanolamine Transferases as Drug Discovery Targets for Therapeutic Treatment of Multi-Drug Resistant Pathogenic Gram-Negative Bacteria

“…Most of these compounds have no known direct mode of action targeting MCR-1. Several promising candidates, including Pterostilbene [ 141 ], Genistein [ 142 ], Phloretin [ 143 ], Osthole [ 144 ], Pogostone [ 145 ], Pingwei Pill [ 146 ], Pyrazolones [ 147 ], and Honokiol [ 148 ], which could improve polymyxin efficacy both in vitro and in vivo, have been found. Molecular simulation and/or molecular docking analyses suggest that most of these compounds, except for Pterostilbene, have the potential to interact with multiple residues in the MCR-1 active site [ 141 , 142 , 143 , 144 , 145 , 146 , 148 ], but further studies are necessary to confirm their direct ability to inhibit MCR-1.…”