title: Synergistic antibacterial effects of herbal extracts and antibiotics on methicillin-resistant Staphylococcus aureus: A computational and experimental study.
abstract: Antibiotic resistance has become a serious global concern, and the discovery of antimicrobial herbal constituents may provide valuable solutions to overcome the problem. In this study, the effects of therapies combining antibiotics and four medicinal herbs on methicillin-resistant Staphylococcus aureus (MRSA) were investigated. Specifically, the synergistic effects of Magnolia officinalis, Verbena officinalis, Momordica charantia, and Daphne genkwa in combination with oxacillin or gentamicin against methicillin-resistant (ATCC43300) and methicillin-susceptible (ATCC25923) S. aureus were examined. In vitro susceptibility and synergistic testing were performed to measure the minimum inhibitory concentration and fractional inhibitory concentration (FIC) index of the antibiotics and medicinal herbs against MRSA and methicillin-susceptible S. aureus. To identify the active constituents in producing these synergistic effects, in silico molecular docking was used to investigate the binding affinities of 139 constituents of the four herbs to the two common MRSA inhibitory targets, penicillin binding proteins 2a (PBP2a) and 4 (PBP4). The physicochemical and absorption, distribution, metabolism, and excretion properties and drug safety profiles of these compounds were also analyzed. D. genkwa extract potentiated the antibacterial effects of oxacillin against MRSA, as indicated by an FIC index value of 0.375. M. officinalis and V. officinalis produced partial synergistic effects when combined with oxacillin, whereas M. charantia was found to have no beneficial effects in inhibiting MRSA. Overall, tiliroside, pinoresinol, magnatriol B, and momorcharaside B were predicted to be PBP2a or PBP4 inhibitors with good drug-like properties. This study identifies compounds that deserve further investigation with the aim of developing therapeutic agents to modulate the effect of antibiotics on MRSA. Impact statement Antibiotic resistant is a well-known threat to global health and methicillin-resistant Staphylococcus aureus is one of the most significant ones. These resistant bacteria kill thousands of people every year and therefore a new effective antimicrobial treatment is necessary. This study identified the herbs and their associated bioactive ingredients that can potential the effects of current antibiotics. These herbs have long history of human usage in China and have well-defined monograph in the Chinese Pharmacopeia. These indicate their relatively high clinical safety and may have a quicker drug development process than that of a new novel antibiotic. Based on the results of this study, the authors will perform further in vitro and animal studies, aiming to accumulate significant data for the application of clinical trial.
authors.affiliation: School of Health Sciences, Macao Polytechnic Institute, Macao 999078, China.
authors.forename: Chiu-Fai
authors.initials: CF
authors.lastname: Kuok
authors.affiliation: School of Health Sciences, Macao Polytechnic Institute, Macao 999078, China.
authors.forename: Sai-On
authors.initials: SO
authors.lastname: Hoi
authors.affiliation: School of Health Sciences, Macao Polytechnic Institute, Macao 999078, China.
authors.forename: Chi-Fai
authors.initials: CF
authors.lastname: Hoi
authors.affiliation: School of Health Sciences, Macao Polytechnic Institute, Macao 999078, China.
authors.forename: Chi-Hong
authors.initials: CH
authors.lastname: Chan
authors.affiliation: School of Health Sciences, Macao Polytechnic Institute, Macao 999078, China.
authors.forename: Io-Hong
authors.initials: IH
authors.lastname: Fong
authors.affiliation: School of Health Sciences, Macao Polytechnic Institute, Macao 999078, China.
authors.forename: Cheong-Kei
authors.initials: CK
authors.lastname: Ngok
authors.affiliation: School of Health Sciences, Macao Polytechnic Institute, Macao 999078, China.
authors.forename: Li-Rong
authors.initials: LR
authors.lastname: Meng
authors.affiliation: School of Health Sciences, Macao Polytechnic Institute, Macao 999078, China.
authors.forename: Pedro
authors.initials: P
authors.lastname: Fong
mesh_terms: D000900:Anti-Bacterial Agents / Q000494:pharmacology*; D032364:Daphne / Q000737:chemistry; D004357:Drug Synergism; D004359:Drug Therapy, Combination; D005839:Gentamicins / Q000494:pharmacology*; D031566:Magnolia / Q000737:chemistry; D055624:Methicillin-Resistant Staphylococcus aureus / Q000187:drug effects*; D008826:Microbial Sensitivity Tests; D062105:Molecular Docking Simulation; D029777:Momordica charantia / Q000737:chemistry; D010068:Oxacillin / Q000494:pharmacology*; D010936:Plant Extracts / Q000494:pharmacology*; D013211:Staphylococcus aureus / Q000187:drug effects; D032412:Verbena / Q000737:chemistry
chemical_list: D000900:Anti-Bacterial Agents; D005839:Gentamicins; D010936:Plant Extracts; D010068:Oxacillin
keywords: Antibiotic resistance; methicillin-resistant Staphylococcus aureus; molecular docking; penicillin binding proteins; synergistic effects; traditional Chinese medicines