Molecular Modification Study On Enhanced Biodegradability Of Fluoroquinolone Antibiotic In Theory

Fluoroquinolones(FQs)are a class of synthetic antibiotics that are widely used.They can effectively inhibit DNA replication and transcription of pathogenic bacteria.Because of their broad antibacterial spectrum and strong antibacterial activity,they are extensively used in the medical industry and aquaculture industry.It is because FQs are widely used that the destruction of the natural environment is also increasing,and it has gradually become a burden to improving the environment.Many problems such as bacterial resistance,groundwater pollution,and difficulty in biodegradation have caused negative effects on human health and the natural environment.The low biodegradability of FQs leads to a very low removal rate of FQs in sewage treatment plants,so the elimination of FQs is difficult.Therefore,this study aims at improving the biodegradability of FQs,and studies the aerobic biodegradability of FQs and the combined aerobic,facultative and anaerobic multi-effect biode’gradability,which is to improve the biodegradability of FQs from the source.According to the research purpose,we constructed a single-effect model and a multi-effect model of FQs biodegradability,aiming to design new environmentally friendly FQs derivatives with high biodegradability,and provide practical theoretical and technical reserves for the replacement of FQs.Based on the FQs biodegradation data obtained by molecular docking,single-effect and multi-effect 1odels were established.The cross-validation q2 of the FQs biodegradability single-effect model is 0.516(>0.5),the optimal principal component,N,is 6,the non-cross validation coefficient,R2,is 0.999(close to 1),the standard error,SEE,is 0.006,and the interactive validation coefficient,r2pred,of the external test set of the model is 0.727(>0.6);q2 of the FQs biodegradability multi-effect model is 0.535(>0.5),N is 5,R2 is 0.994(close to 1),SEE is 0.014,and r2pred is 0.773(>0.6).Therefore,both models have reliable prediction ability,good fitting ability,good robustness and external prediction ability.The single-effect model CoMFA force field analysis and contour maps analysis were used to find the modification sites.With Levofloxacin(LEV)as the target molecule,new FQs derivatives were designed through substitution reactions,and a total of 35 new molecules were designed.After the evaluation of genotoxicity,bioconcentration and photodegradation,2-Fluorine,5-Aldehyde,with higher biodegradability(increased by 27.85%),higher genotoxicity(increased by 1.03%),higher photodegradation(increased by 10.70%)and lower bioconcentration(decreased by 20.44%),was identified as the most environmentally friendly fluoroquinolone derivative.Using 2D-QSAR model and sensitivity analysis method to analyze,it was found that q+of FQs was the main parameter that affected the biodegradability of FQs.Additionally,we inferred and analyzed the pathways and biodegradation mechanisms of the derivatives 2-Fluorine,5-Aldehyde molecules by microorganisms.The total energy barrier value of the pathway with the lowest total energy barrier of biodegradation was reduced by 32.07%,which was basically consistent with the enhancement of biodegradability of 2-Fluorine,5-Aldehyde.Accordingly,2-Fluorine,5-Aldehyde was demonstrated as a biodegradable and environmentally friendly fluoroquinolone derivative that can be reserved for future use.By using the FQs multi-effect biodegradability model,Gatifloxacin(GAT)was used as the target molecule to design and screen 25 FQs derivatives,aiming to screen out environmentally friendly FQs derivatives with high combined biodegradability,Finally,1-Butylbenzene-3-Fluorine-GAT molecule was successfully screened.The combined biodegradation of the 1-Butylbenzene-3-Fluorine-GAT was increased by 14.06%,and its aerobic,facultative and anaerobic biodegradation performance was increased by 31.33%,36.54%and 35.50%,the performance improvement was in line with the equal weighting set by the averaging.In addition,molecular docking,molecular dynamics technology and 2D-QSAR methods were used to analyze the mechanism of FQs derivatives that were easy to biodegrade.Molecular dynamics calculations showed that the 1-Butylbenzene-3-Fluorine-GAT binding energy ΔGb value was lower than the target molecule GAT(the lower the value of ΔGb,the stronger the binding ability),indicating that it had a stronger affinity for degrading enzymes.The ΔGb of 1-Butylbenzene-3-Fluorine-GAT with the above three enzymes decreased by 58.05%,88.20%and 54.53%respectively,which was the same as the improvement of molecular docking score.Moreover,through 2D-QSAR model and sensitivity analysis,it was found that the electronic parameter q+of FQs was the most sensitive parameter affecting its biodegradability.