Special Issue "Recent Advances towards the Design of Environment-Friendly Quinolone Antibiotics based on Theoretical Approach"

A special issue of International Journal of Environmental Research and Public Health (ISSN 1660-4601). This special issue belongs to the section "Environmental Science and Engineering".

Deadline for manuscript submissions: closed (30 April 2020).

Special Issue Editor

Prof. Yu Li
Website SciProfiles
Guest Editor
College of Environmental Science and Engineering, North China Electric Power University, Beijing, China
Interests: environmental chemistry; theoretical chemistry; environmental pollution control; pollutant form migration and transformation; environmental planning and impact assessment

Special Issue Information

Dear Colleagues,

In our society, many natural and synthetic compounds are widely used in the medical field. Antibiotics, a product of both natural and synthetic, have been developed to treat various bacterial infections or inhibit pathogenic microbial infections, such as intestinal infections, respiratory infections, and other diseases. Quinolones are a kind of antibiotic with keto acid as the common framework. They have been widely used for the clinical treatment of human and veterinary diseases because of their broad spectrum of antibacterial activity, high antibacterial action, and strong tissue penetration. Unfortunately, the extensive use of quinolones leads to the continuous infusion of quinolones and their active ingredients into the water, making them frequently detected in environmental samples. The persistence of quinolones residues in the aquatic system could lead to a serious and unpredictable threat to the ecosystem and human health.

Quinolones enter into the water environment through the direct discharge of human and animal feces, and the aquaculture industry’s drug use and wastewater. This kind of water environment contains various toxic organic compounds, which are difficult to degrade and have high concentrations of active ingredients. Although the water has been heavily treated beforehand, the components of quinolones and their residues still have a strong inhibition on the growth of microorganisms in the wastewater. Due to the characteristics of large water quality and water fluctuation, quinolones will continue to migrate and diffuse in water.

Aside from the low degradability of quinolones, their metabolites also have the same or even stronger toxicity than the quinolones, and may be transformed into antibiotic drugs. For example, moxifloxacin, as a kind of quinolone, can produce chlorinated products with higher genotoxicity in a low-dose chlorination reaction. A high-dose chlorination reaction, on the other hand, can easily produce many chlorinated products with an isomeric effect.

To overcome the above problems, the aim of this Special Issue is to summarize recent research findings in the field of rational drug design through using the molecular model of the structural characteristics of the ligands and receptors. Thus, the inclusion of degradation studies, metabolites analysis, environmental pollution, adverse reaction, drug design, and theoretical studies of the structure–activity relationship of quinolones are welcome. The critical visions from the contributors will help us to understand and emphasize the advances in our knowledge of the degradation of quinolones and their metabolites.

Prof. Yu Li
Guest Editor

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Keywords

  • Modification of quinolone antibiotics to be environment-friendly based on a theoretical approach
  • Assessment on the environmental pollution control and human health effect of antimicrobial/antibiotics
  • Degradation of antimicrobial/antibiotic residues in the environment, such as biodegradation and photodegradation
  • Detection aspects of antimicrobial/antibiotic residues in the environment
  • Assessment of the risks of various antimicrobial/antibiotic conversion products in the environment or the combined toxicity to the environment and organisms
  • Reduction of multiple adverse reactions of antimicrobial/antibiotic in the environment
  • Remediation of antimicrobial/antibiotic metal resistant genes/bacteria in the environment, focusing on issues related to antimicrobial/antibiotic residues/resistance in the environment
  • Toxic mechanism of antimicrobial/antibiotics

Published Papers (5 papers)

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Research

Open AccessArticle
Integration of Fuzzy Matter-Element Method and 3D-QSAR Model for Generation of Environmentally Friendly Quinolone Derivatives
Int. J. Environ. Res. Public Health 2020, 17(9), 3239; https://doi.org/10.3390/ijerph17093239 - 06 May 2020
Abstract
The environmental pollution of quinolone antibiotics (QAs) has caused rising public concern due to their widespread usage. In this study, Gaussian 09 software was used to obtain the infrared spectral intensity (IRI) and ultraviolet spectral intensity (UVI) of 24 QAs based on the [...] Read more.
The environmental pollution of quinolone antibiotics (QAs) has caused rising public concern due to their widespread usage. In this study, Gaussian 09 software was used to obtain the infrared spectral intensity (IRI) and ultraviolet spectral intensity (UVI) of 24 QAs based on the Density Functional Theory (DFT). Rather than using two single-factor inputs, a fuzzy matter-element method was selected to calculate the combined effects of infrared and ultraviolet spectra (CI). The Comparative Molecular Field Analysis (CoMFA) was then used to construct a three-dimensional quantitative structure–activity relationship (3D-QSAR) with QAs’ molecular structure as the independent variable and CI as the dependent variable. Using marbofloxacin and levofloxacin as target molecules, the molecular design of 87 QA derivatives was carried out. The developed models were further used to determine the stability, functionality (genetic toxicity), and the environmental effects (bioaccumulation, biodegradability) of these designed QA derivatives. Results indicated that all QA derivatives are stable in the environment with their IRI, UVI, and CI enhanced. Meanwhile, the genetic toxicity of the 87 QA derivatives increased by varying degrees (0.24%–29.01%), among which the bioaccumulation and biodegradability of 43 QA derivatives were within the acceptable range. Through integration of fuzzy matter-element method and 3D-QSAR, this study advanced the QAs research with the enhanced CI and helped to generate the proposed environmentally friendly quinolone derivatives so as to aid the management of this class of antibiotics. Full article
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Open AccessArticle
A Double-Activity (Green Algae Toxicity and Bacterial Genotoxicity) 3D-QSAR Model Based on the Comprehensive Index Method and Its Application in Fluoroquinolones’ Modification
Int. J. Environ. Res. Public Health 2020, 17(3), 942; https://doi.org/10.3390/ijerph17030942 - 03 Feb 2020
Cited by 1
Abstract
The comparative molecular similarity index analysis (CoMSIA) model of double-activity quinolones targeting green algae toxicity and bacterial genotoxicity (8:2) was constructed in this paper on the basis of the comprehensive index method. The contour maps of the model were analyzed for molecular modifications [...] Read more.
The comparative molecular similarity index analysis (CoMSIA) model of double-activity quinolones targeting green algae toxicity and bacterial genotoxicity (8:2) was constructed in this paper on the basis of the comprehensive index method. The contour maps of the model were analyzed for molecular modifications with high toxicities. In the CoMSIA model, the optimum number of components n was 7, the cross-validated q2 value was 0.58 (>0.5), the standard deviation standard error of estimate (SEE) was 0.02 (<0.95), F was 1265.33, and the non-cross-validated R2 value was 1 (>0.9), indicating that the model had a good fit and predicting ability. The scrambling stability test parameters Q2, cross-validated standard error of prediction (cSDEP), and dq2/dr2yy were 0.54, 0.25, and 0.8 (<1.2), respectively, indicating that the model had good stability. The external verification coefficient r2pred was 0.73 (>0.6), and standard error of prediction (SEP) was 0.17, indicating that the model had a good external prediction ability. The contribution rates of the steric fields, electrostatic fields, hydrophobic fields, hydrogen bond donor, and acceptor fields were 10.9%, 19.8%, 32.7%, 13.8%, and 22.8%, respectively. Large volume groups were selected for modification of ciprofloxacin (CIP), and the derivatives with increased double-activity characterization values were screened; the increase ratio ranged from 12.31–19.09%. The frequency of derivatives were positive and total energy, bioaccumulation, and environmental persistence was reduced, indicating that the CIP derivatives had good environmental stability and friendliness. Predicted values and CoMSIA model constructed of single activities showed that the CoMSIA model of double activities had accuracy and reliability. In addition, the total scores of the derivatives docking with the D1 protein, ferredoxin-NADP (H) reductases (FNRs), and DNA gyrase increased, indicating that derivatives can be toxic to green algae by affecting the photosynthesis of green algae. The mechanism behind the bactericidal effect was also explained from a molecular perspective. Full article
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Open AccessArticle
Combined 2D-QSAR, Principal Component Analysis and Sensitivity Analysis Studies on Fluoroquinolones’ Genotoxicity
Int. J. Environ. Res. Public Health 2019, 16(21), 4156; https://doi.org/10.3390/ijerph16214156 - 28 Oct 2019
Cited by 4
Abstract
In this paper, two-dimensional quantitative structure–activity relationship (2D-QSAR) and principal component analysis (PCA) methods were employed to screen the main parameters affecting the genotoxicity of fluoroquinolones (FQs), and the rules affecting the genetic toxicity of FQs were investigated by combining 2D-QSAR and PCA [...] Read more.
In this paper, two-dimensional quantitative structure–activity relationship (2D-QSAR) and principal component analysis (PCA) methods were employed to screen the main parameters affecting the genotoxicity of fluoroquinolones (FQs), and the rules affecting the genetic toxicity of FQs were investigated by combining 2D-QSAR and PCA with the sensitivity analysis method. First, four types of parameters were calculated, namely, the geometric parameters (7), electronic parameters (5), physical and chemical parameters (8), and spectral parameters (7), but the physical and chemical parameters heat of formation (HF) and critical volume (CV) were excluded after the establishment of the 2D-QSAR model. Then, after PCA, it was found that the first principal component represented the main driving factors affecting the molecular genetic toxicity of FQs. In addition, after comprehensive analysis of the factor loading of the first, second, and third principal components, seven parameters affecting the genotoxicity of the FQs were screened out, namely, total energy (TE), critical temperature (CT), and molecular weight (Mol Wt) (increased with increasing genotoxicity of the FQs) and steric parameter (MR), quadrupole moment QXX (QXX), quadrupole moment QYY (QYY), and boiling point (BP) (decreased with increasing genotoxicity of the FQs); the above key parameters were also verified by sensitivity analysis. The obtained rules could be used to determine the substitution sites and the substitution groups associated with higher genotoxicity in the process of FQ modification, and these rules agreed well with the hologram quantitative structure–activity relationship (HQSAR) model. Finally, it was also found through SPSS analysis that the parameters screened in this paper were significantly correlated with FQ derivatives’ genetic toxicity. Full article
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Open AccessArticle
Molecular Modification of Fluoroquinolone-Biodegrading Enzymes Based on Molecular Docking and Homology Modelling
Int. J. Environ. Res. Public Health 2019, 16(18), 3407; https://doi.org/10.3390/ijerph16183407 - 13 Sep 2019
Cited by 2
Abstract
To improve the biodegradation efficiency of fluoroquinolone antibiotics during sewage treatment, fluoroquinolone aerobic, anaerobic and facultative degrading enzymes for fluoroquinolone degradation were modified by molecular docking and homology modelling. First, amino acid residues of the binding sites of degrading enzymes for the target [...] Read more.
To improve the biodegradation efficiency of fluoroquinolone antibiotics during sewage treatment, fluoroquinolone aerobic, anaerobic and facultative degrading enzymes for fluoroquinolone degradation were modified by molecular docking and homology modelling. First, amino acid residues of the binding sites of degrading enzymes for the target fluoroquinolones ciprofloxacin (CIP), norfloxacin (NOR) and ofloxacin (OFL) were analysed by the molecular docking method. The hydrophobic amino acid residues within 5 Å of the target fluoroquinolone molecules were selected as the modification sites. The hydrophobic amino acid residues at the modified sites were replaced by the hydrophilic amino acid residues, and 150 amino acid sequence modification schemes of the degrading enzymes were designed. Subsequently, a reconstruction scheme of the degrading enzyme amino acid sequence reconstruction scheme was submitted to the SWISS-MODEL server and a selected homology modelling method was used to build a new structure of the degrading enzyme. At the same time, the binding affinities between the novel degrading enzymes and the target fluoroquinolones (represented by the docking scoring function) were evaluated by the molecular docking method. It was found that the novel enzymes can simultaneously improve the binding affinities for the three target fluoroquinolones, and the degradation ability of the six modification schemes was increased by more than 50% at the same time. Among the novel enzymes, the affinity effect of the novel anaerobic enzyme (6-1) with CIP, NOR and OFL was significantly increased, with increases of 129.24%, 165.06% and 169.59%, respectively, followed by the facultative enzyme and aerobic enzyme. In addition, the designed degrading enzymes had certain selectivity for the degradation of the target quinolone. Among the novel enzymes, the binding affinities of the novel anaerobic enzyme (6-3) and CIP, the novel aerobic enzyme (3-6) and NOR, and the novel facultative enzyme (13-6) and OFL were increased by 149.71%, 178.57% and 297.12% respectively. Calculations using the Gaussian09 software revealed that the degradation reaction barrier of the novel degrading enzyme (7-1) and CIP NOR and OFL decreased by 37.65 kcal·mol−1, 6.28 kcal·mol−1 and 6.28 kcal·mol−1, respectively, which would result in efficient degradation of the target fluoroquinolone molecules. By analysing the binding affinity of the degrading enzymes before and after the modification with methanol, it was further speculated that the degradation effect of the modified aerobic degrading enzymes on organic matter was lower than that before the modification, and the increase or decrease in the degradation effect was less than 10%. The mechanism analysis found that the interaction between the modified amino acid residues of the degrading enzymes and the fluoroquinolone molecules increased. The average distance between the amino acid residues and the fluoroquinolone molecules represented a comprehensive affinity effect, and its value was positively correlated with the degradation effect of the novel degrading enzymes. Full article
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Open AccessArticle
Fuzzy Comprehensive Evaluation Assistant 3D-QSAR of Environmentally Friendly FQs to Reduce ADRs
Int. J. Environ. Res. Public Health 2019, 16(17), 3161; https://doi.org/10.3390/ijerph16173161 - 29 Aug 2019
Cited by 7
Abstract
Most studies on adverse drug reactions (ADRs) of fluoroquinolones (FQs) have focused on the mechanisms of single ADRs, and no quantitative structure–activity relationship (QSAR) method studies have been carried out that combine several ADRs of FQs. In this study, an improved three-dimensional (3D) [...] Read more.
Most studies on adverse drug reactions (ADRs) of fluoroquinolones (FQs) have focused on the mechanisms of single ADRs, and no quantitative structure–activity relationship (QSAR) method studies have been carried out that combine several ADRs of FQs. In this study, an improved three-dimensional (3D) QSAR method was established using fuzzy comprehensive evaluation. This method could simultaneously consider three common ADRs of FQs using molecular parameters. The improved method could comprehensively predict three ADRs of FQs and provide direction for the development of new drugs with lower ADRs than the originals. According to the improved method, 48 derivatives with lower ADRs (decreased by 4.86% to 50.92%) were designed from pazufloxacin. Three derivatives with a higher genotoxicity, higher photodegradation, and lower bioconcentration than pazufloxacin were selected using the constructed QSAR methods of the FQs. Finally, three traditional 3D-QSAR methods of single ADR were constructed to validate the improved method. The improved method was reasonable, with a relative error range of 0.96% to 4.30%. This study provides valuable reference data and will be useful for the development of strategies to produce new drugs with few ADRs. In the absence of complementary biological studies of these adverse drug reactions, the results reported here may be quite divergent from those found in humans or experimental animals in vivo. One major reason for this is that many adverse drug reactions are dependent upon enzyme-catalyzed metabolic activation (toxication) or on non-enzymatic conversion to toxic products and are not due to the parent drug moiety. Full article
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