The Effects Of Melatonin On Antibiotic-mediated Lethality

The misuse and overuse of antibiotics lead to the emergence of a large number of resistant and/or tolerant bacteria.Bacterial resistance and tolerance to antimicrobials have become a huge problem that needs to be solved urgently.In the sterilization process of bactericidal antibiotics,besides direct killing bacteria by binding to their respective target sites,antimicrobials can also induce the intracellular accumulation of reactive oxygen species(ROS).Elevated levels of ROS can damage bacterial cell components and kill bacteria.Melatonin is an excellent antioxidant.In eukaryotic organisms,melatonin has been reported to remove ROS from cells to reduce oxidative stress.At the same time,melatonin is also considered to have a good preventive and therapeutic effect in many clinical diseases.It has been widely used as dietary supplements to treat sleep-related ailment.Studying the effect of subinhibitory concentration of melatonin on antibiotic killing in this thesis project will not only help obtain a safe free radical scavenger to study ROS-related bacterial tolerance,but it can also provide good advice for patients with bacterial infections to consume antioxidants during antimicrobial therapyIn the present work,through the study of Escherichia coli and several other common nosocomial pathogens,we found that melatonin has differential effects on antimicrobial lethality among various drug-bacterium combinations.In Escherichia coli and Klebsiella pneumoniae,high subinhibitory concentrations of melatonin can eliminate ROS in bacteria,which significantly increases the tolerance of bacteria to antibiotics and protects bacteria from being killed by antibiotics.Solvent dimethyl sulfoxide(DMSO),with its own permeability enhancing effect,can further increase the protective effect of melatonin on killing by aminoglycoside antibiotic,kanamycin,and by quinolone antimicrobials,ciprofloxacin and oxolinic acid in Escherichia coli and Klebsiella pneumonia.Subinhibitory concentrations of melatonin in Escherichia coli can not only reduce the accumulation of ROS and reduce killing during antimicrobial treatment,but they can also reduce ROS-mediated,post-stress programmed cell death(PCD)after antimicrobials have been removed.In Acinetobacter baumannii,the results were opposite to those observed in Escherichia coli and Klebsiella pnezumoniae.Adding high subinhibitory concentrations of melatonin not only increased the sensitivity of Acinetobacter/bamannii to meropenem,but it also promoted the killing effect of ciprofloxacin.The behavior of Pseudomonas aeruginosa and Staphylococcus aureus appeared that the addition of subinhibitory concentration of melatonin had no significant effect on the killing effect of antibiotics.This may be related to the antimicrobial activity of melatonin,the specificity of the bacterial strain and its own metabolism,but the specific mechanism remains to be further explored.