Using the hologram quantitative structure-activity relationship (HQSAR) method, a quantitative model of the structure-activity relationship between the genotoxicity of quinolones towards gram-negative bacteria and structure of quinolones is constructed. A series of novel quinolones are designed, and 4 environmentally friendly quinolone derivatives are finally selected, because of their enhanced genotoxicity towards gram-negative/positive bacteria, decreased bioconcentration and increased photodegradability and biodegradability. The mechanisms underlying the genotoxicity of quinolones and its derivatives are analysed based on amino acid residues and molecular interactions. Three hydrophilic amino acids [arginine (ARG), asparagine (ASN) and aspartic acid (ASP)] play important roles in the antibacterial effects of quinolones. The introduction of highly hydrophilic groups into the C-7 position of amifloxacin (AMI) not only improved the stability of the AMI derivative-topoisomerase IV-DNA complex but also improved the antibacterial activities of AMI derivatives.
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Aldred KJ, Kerns RJ, Osheroff N (2014) Mechanism of quinolone action and resistance. Biochemistry 53(10):1565–1574
Amin SA, Adhikari N, Gayen S, Jha T (2017) First report on the structural exploration and prediction of new BPTES analogs as glutaminase inhibitors. J Mol Struct 1143:49–64
Araujo CAVD, Maciel GM, Rodrigues EA, Silva LL, Oliveira RF, Brugnari T, Peralta RM, Souza CGMD (2017) Simultaneous removal of the antimicrobial activity and toxicity of sulfamethoxazole and trimethoprim by white rot fungi. Water Air Soil Pollut 228(9):341
Bisacchi GS (2015) Origins of the quinolone class of antibacterials: an expanded “discovery story”. J Med Chem 58(12):4874–4882
Boulanger B, Vargo JD, Schnoor JL, Hornbuckle KC (2005) Evaluation of perfluorooctane surfactants in a wastewater treatment system and in a commercial surface protection product. Environ Sci Technol 39(15):5524–5530
Bush BL, Nachbar RB Jr (1993) Sample-distance partial least squares: PLS optimized for many variables, with application to CoMFA. J Comput Aided Mol Des 7(5):587–619
Cawley GC, Talbot NL (2004) Fast exact leave-one-out cross-validation of sparse least-squares support vector machines. Neural Netw 17(10):1467–1475
Centers for Disease Control and Prevention (2007) Preliminary food net data on the incidence of infection with pathogens transmitted commonly through food 10 states. MMWR Morb Mortal Wkly Rep 56(14):336–339
Clark M, Cramer RD, Opdenbosch NV (1989) Validation of the general purpose Tripos 5.2 force field. J Comput Chem 10(8):982–1012
Clark M, Iii RDC, Jones DM, Patterson DE, Simeroth PE (1990) Comparative molecular field analysis (CoMFA). 2. Toward its use with 3D-structural databases. Tetrahedron Comput Methodol 3(1):47–59
CNINFO (2018) 2017-2023 China antibiotics market in-depth survey and future development trend report. Available at: http://www.cninfo360.com/yjbg/yyhy/hxy/20170213/522969.html. February 2019
Doddareddy MR, Lee YJ, Cho YS, Choi KI, Koh HY, Pae AN (2004) Hologram quantitative structure activity relationship studies on 5-HT6 antagonists. Bioorg Med Chem 12:3815–3824
Ewing TJA, Makino S, Skillman AG, Kuntz ID (2001) DOCK 4.0: search strategies for automated molecular docking of flexible molecule database. J Comput Aided Mol Des 15(5):411–428
Flower DR (1998) On the properties of bit string-based measures of chemical similarity. J Chem Inf Comput Sci 38(3):379–386
Fortunato F, Martinelli D, Cappelli MG, Cozza V, Prato R (2015) Impact of pneumococcal conjugate universal routine vaccination on pneumococcal disease in Italian children. J Immunol Res 2015(12):206757
Gao L, Shi Y, Li W, Niu H, Liu J, Cai Y (2012) Occurrence of antibiotics in eight sewage treatment plants in Beijing, China. Chemosphere 86(6):665–671
Gasteiger J, Marsili M (1980) Iterative partial equalization of orbital electronegativity—a rapid access to atomic charges. Tetrahedron 36:3219–3228
Ghate M, Jain S (2014) Fragment based HQSAR modeling and docking analysis of conformationally rigid 3-azabicyclo [3.1.0] hexane derivatives to design selective DPP-4 inhibitors. Lett Drug Des Discov 11(2):184–198
Grant EB, Foleno BD, Goldschmidt R, Hilliard JJ, Lin SH et al (2014) 7-(4-Alkylidenylpiperidinyl)-quinolone bacterial topoisomerase inhibitors. Bioorg Med Chem Lett 24(23):5502–5506
Hu XE, Kim NK, Gray JL, Almstead JK, Seibel WL, Ledoussal B (2003) Discovery of (3S)-amino-(4R)-ethylpiperidinyl quinolones as potent antibacterial agents with a broad spectrum of activity and activity against resistant pathogens. J Med Chem 46(17):3655–3661
Kim KR, Owens G, Kwon SI, So KH, Lee DB, Yong SO (2011) Occurrence and environmental fate of veterinary antibiotics in the terrestrial environment. Water Air Soil Pollut 214(1–4):163–174
LaCrue AN, Saenz FE, Cross RM, Cross RM, Udenze KO, Monastyrskyi A, Stein S, Mutka TS, Manetsch R, Kyle DE (2013) 4(1H)-Quinolones with liver stage activity against Plasmodium berghei. Antimicrob Agents Chemother 57(1):417–424
Leung HW, Minh TB, Murphy MB, Lam JC, So MK, Martin M, Lam PK, Richardson BJ (2012) Distribution, fate and risk assessment of antibiotics in sewage treatment plants in Hong Kong, South China. Environ Int 42:1): 1–1): 9
Li JZ, Li SY, Bai CL, Liu HX, Gramatica P (2013) Structural requirements of 3-carboxyl-4(1H)-quinolones as potential antimalarials from 2D and 3D QSAR analysis. J Mol Graph Model 44(7):266–277
Li M, Wei DB, Zhao HM, Du YG (2014) Genotoxicity of quinolones: substituents contribution and transformation products QSAR evaluation using 2D and 3D models. Chemosphere 95:220–226
Lin H, Dyar OJ, Rosales-Klintz S, Zhang J, Tomson G, Hao M, Stålsby Lundborg C (2016) Trends and patterns of antibiotic consumption in Shanghai municipality, China: a 6 year surveillance with sales records, 2009–1. J Antimicrob Chemother 71(6):1723–1729
Liu DY (2014) (H2O)10-(glycine)n(n=1-3) complex: a theoretical investigation of configurations and properties. Dissertation, Hebei Normal University (in Chinese)
Luan G, Drlica K (2018) Fluoroquinolone-gyrase-DNA cleaved complexes. Methods Mol Biol 1703:269–281
Sayed M, Khan JA, Shah LA, Shah NS, Khan HM, Rehman F, Khan AR, Khan AM (2016) Degradation of quinolone antibiotic, norfloxacin, in aqueous solution using gamma-ray irradiation. Environ Sci Pollut R 23(13):13155–13168
Sukul P, Spiteller M (2007) Fluoroquinolone antibiotics in the environment. Rev Environ Contam Toxicol 191:131–162
Tong JB, Lei S, Qin SS, Wang Y (2018) QSAR studies of TIBO derivatives as HIV-1 reverse transcriptase inhibitors using HQSAR, CoMFA and CoMSIA. J Mol Struct 1168:56–64
Wang WF (2007) Quantitative structure-effect relationship of quinolones and behavior of genotoxic substances in water environment. Dissertation, Henan Normal University (in Chinese)
Wang XL, Chu ZH, Yang JW, Li Y (2017) Pentachlorophenol molecule design with lower bioconcentration through 3D-QSAR associated with molecule docking. Environ Sci Pollut R 24(32):1–12
Wold S, Sjöström M, Eriksson L (2001) PLS-regression: a basic tool of chemometrics. Chemom Intell Lab Syst 58(2):109–130
Xiao W (2014) Theoretical research of hydrogen bond and intermolecular weak interactions, electronic characteristics and excitation state of base-pairs. Dissertation, Southwest University (in Chinese)
Yang WH, Yu HX, Wang M (2015) Interaction between polybrominated diphenyl ether derivatives and human placental aromatase by molecular docking. Environ Chem 34(5):904–910 (in Chinese)
Ye M, Dawson MI (2009) Studies of cannabinoid-1 receptor antagonists for the treatment of obesity: hologram QSAR model for biarylpyrazolyl oxadiazole ligands. Bioorg Med Chem Lett 19(12):3310–3315
Zhang R, Zhang G, Zheng Q, Tang J, Chen Y, Xu W, Zou Y, Chen X (2012) Occurrence and risks of antibiotics in the Laizhou Bay, China: impacts of river discharge. Ecotoxicol Environ Safe 80(2):208–215
Zhang QQ, Ying GG, Pan CG, Liu YS, Zhao JL (2015) A comprehensive evaluation of antibiotics emission and fate in the river basins of China: source analysis, multimedia modelling, and linkage to bacterial resistance. Environ Sci Technol 49(11):6772–6782
Zhao XH, Zhao YY, Ren ZX, Li Y (2018a) Combined QSAR/QSPR and molecular docking study on fluoroquinolones to reduce biological enrichment. Comput Biol Chem 79:177–184
Zhao XH, Chu ZH, Li Y (2018b) Molecular design of lower photodegradation fluoroquinolone antibiotics and their photolysis paths inference. Chem J Chin Univ 39:2707–2718 (in Chinese)
Zhou PA (2010) Theoretical studies of intermolecular interactions: hydrogen bond, van der Waals contact and halogen bond. Dissertation, Lanzhou University (in Chinese)
This research was supported by the Fundamental Research Funds for the Central Universities in 2013 (grant no. JB2013146) and the Key Projects in the National Science and Technology Pillar Program in the Eleventh Five-Year Plan Period (grant no. 2008BAC43B01).
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Zhao, X., Wang, X. & Li, Y. Combined HQSAR method and molecular docking study on genotoxicity mechanism of quinolones with higher genotoxicity. Environ Sci Pollut Res 26, 34830–34853 (2019). https://doi.org/10.1007/s11356-019-06482-3
- Genotoxic mechanism
- Molecular design
- Molecular docking