Covid-19 Research

In silico Screening of Approved Drugs to Describe Novel E. coli DNA Gyrase A Antagonists

Start Submission

The alarming multiple drug resistance developed by Escherichia coli towards the routine conventional antibiotics owing to their non-judicious usage is fast becoming a tough menace. This necessitates the urgent unleashing of novel and diverse strategies and antibacterial compounds. Since finding a new antibiotic from the scratch, followed by endless clinical trials is exceedingly time-consuming, a powerful alternate strategy of CADD coupled with repurposing the available drugs could save precious time and money. DNA gyrases (topoisomerase II) of E.coli are among the promising new drug targets. The interface between the N-terminal domain of gyrA and C- terminal domain of gyrB which is targeted by most of the available inhibitory drugs, is of particular interest. Crucial active site residues within the N-terminal domain of gyrA were delineated through a literature search. FDA approved drugs were docked using FlexX on the receptors created around the co-crystallized reference ligand. Based on the docking scores and interactions with crucial residues, 12 leads were shortlisted, namely ceforanide, tetrahydrofolic acid, azlocillin, cefazolin, adenosine triphosphate, cefixime, dihydronicotinamide adenine dinucleotide, moxalactam, leucal, cromoglicic acid, cefotetan, and cedax. Surprisingly quinolones, which are approved inhibitors of gyrases were not picked up in the top leads, rather, the most dominant class of molecules that docked successfully was cephalosporin. Our results indicated that these cephalosporins, as well as the other shortlisted leads, could be further optimized and validated through in-vitro experiments for their potential as gyraseA antagonists. Hence the present study holds immense promise in combating MDR of human bacterial pathogens.

Rakhi Chandran, Archana Ayyagari, Prerna Diwan, Sanjay Gupta and Vandana Gupta*
Volume1-Issue6 | Published: 2020-10-26

FullText HTML FullText PDF


  1. Mellata M. Human and avian extraintestinal pathogenic Escherichia coli: infections, zoonotic risks, and antibiotic resistance trends. Foodborne Pathog Dis. 2013 Nov;10(11):916-32. doi: 10.1089/fpd.2013.1533. Epub 2013 Aug 20. PMID: 23962019; PMCID: PMC3865812.
  2. Alanazi MQ, Alqahtani FY, Aleanizy FS. An evaluation of E. coli in urinary tract infection in emergency department at KAMC in Riyadh, Saudi Arabia: retrospective study. Ann Clin Microbiol Antimicrob. 2018 Feb 9;17(1):3. doi: 10.1186/s12941-018-0255-z. PMID: 29422058; PMCID: PMC5806437.
  3. Hernaiz-Leonardo JC, Golzarri MF, Cornejo-Juárez P, Volkow P, Velázquez C, Ostrosky-Frid M, Vilar-Compte D. Microbiology of surgical site infections in patients with cancer: A 7-year review. Am J Infect Control. 2017 Jul 1;45(7):761-766. doi: 10.1016/j.ajic.2017.02.023. Epub 2017 Apr 3. PMID: 28385464.
  4. Xiao T, Chen LP, Liu H, Xie S, Luo Y, Wu DC. The Analysis of Etiology and Risk Factors for 192 Cases of Neonatal Sepsis. Biomed Res Int. 2017;2017:8617076. doi: 10.1155/2017/8617076. Epub 2017 Jul 3. PMID: 28758124; PMCID: PMC5512054.
  5. Pandey N, Cascella M. Beta Lactam Antibiotics. In: Stat Pearls. Treasure Island (FL): Star Pearls Publishing; 2020.
  6. Bassetti M, Poulakou G, Ruppe E, Bouza E, Van Hal SJ, Brink A. Antimicrobial resistance in the next 30 years, humankind, bugs and drugs: a visionary approach. Intensive Care Med. 2017 Oct;43(10):1464-1475. doi: 10.1007/s00134-017-4878-x. Epub 2017 Jul 21. PMID: 28733718.
  7. McDanel J, Schweizer M, Crabb V, Nelson R, Samore M, Khader K, Blevins AE, Diekema D, Chiang HY, Nair R, Perencevich E. Incidence of Extended-Spectrum β-Lactamase (ESBL)-Producing Escherichia coli and Klebsiella Infections in the United States: A Systematic Literature Review. Infect Control Hosp Epidemiol. 2017 Oct;38(10):1209-1215. doi: 10.1017/ice.2017.156. Epub 2017 Jul 31. PMID: 28758612.
  8. Pitout JD, DeVinney R. Escherichia coli ST131: a multidrug-resistant clone primed for global domination. F1000Res. 2017 Feb 28;6:F1000 Faculty Rev-195. doi: 10.12688/f1000research.10609.1. PMID: 28344773; PMCID: PMC5333602.
  9. Yong D, Toleman MA, Giske CG, Cho HS, Sundman K, Lee K, Walsh TR. Characterization of a new metallo-beta-lactamase gene, bla(NDM-1), and a novel erythromycin esterase gene carried on a unique genetic structure in Klebsiella pneumoniae sequence type 14 from India. Antimicrob Agents Chemother. 2009 Dec;53(12):5046-54. doi: 10.1128/AAC.00774-09. Epub 2009 Sep 21. PMID: 19770275; PMCID: PMC2786356.
  10. Ribeiro da Cunha B, Fonseca LP, Calado CRC. Antibiotic Discovery: Where Have We Come from, Where Do We Go? Antibiotics (Basel). 2019 Apr 24;8(2):45. doi: 10.3390/antibiotics8020045. PMID: 31022923; PMCID: PMC6627412.
  11. Goodlet KJ, Nicolau DP, Nailor MD. Ceftolozane/tazobactam and ceftazidime/avibactam for the treatment of complicated intra-abdominal infections. Ther Clin Risk Manag. 2016 Dec 1;12:1811-1826. doi: 10.2147/TCRM.S120811. PMID: 27942218; PMCID: PMC5140030.
  12. Asadi A, Abdi M, Kouhsari E, Panahi P, Sholeh M, Sadeghifard N, Amiriani T, Ahmadi A, Maleki A, Gholami M. Minocycline, focus on mechanisms of resistance, antibacterial activity, and clinical effectiveness: Back to the future. J Glob Antimicrob Resist. 2020 Sep;22:161-174. doi: 10.1016/j.jgar.2020.01.022. Epub 2020 Feb 12. PMID: 32061815.
  13. Johura FT, Tasnim J, Barman I, Biswas SR, Jubyda FT, Sultana M, George CM, Camilli A, Seed KD, Ahmed N, Alam M. Colistin-resistant Escherichia coli carrying mcr-1 in food, water, hand rinse, and healthy human gut in Bangladesh. Gut Pathog. 2020 Jan 27;12:5. doi: 10.1186/s13099-020-0345-2. PMID: 32002025; PMCID: PMC6986151.
  14. Hearnshaw SJ, Edwards MJ, Stevenson CE, Lawson DM, Maxwell A. A new crystal structure of the bifunctional antibiotic simocyclinone D8 bound to DNA gyrase gives fresh insight into the mechanism of inhibition. J Mol Biol. 2014 May 15;426(10):2023-33. doi: 10.1016/j.jmb.2014.02.017. Epub 2014 Mar 1. PMID: 24594357; PMCID: PMC4018983.
  15. Vanden Broeck A, Lotz C, Ortiz J, Lamour V. Cryo-EM structure of the complete E. coli DNA gyrase nucleoprotein complex. Nat Commun. 2019 Oct 30;10(1):4935. doi: 10.1038/s41467-019-12914-y. PMID: 31666516; PMCID: PMC6821735.
  16. Priyanka, Singh V, Ekta, Katiyar D. Synthesis, antimicrobial, cytotoxic and E. coli DNA gyrase inhibitory activities of coumarinyl amino alcohols. Bioorg Chem. 2017 Apr;71:120-127. doi: 10.1016/j.bioorg.2017.01.019. Epub 2017 Feb 1. PMID: 28196603.
  17. Tomašič T, Barančoková M, Zidar N, Ilaš J, Tammela P, Kikelj D. Design, synthesis, and biological evaluation of 1-ethyl-3-(thiazol-2-yl)urea derivatives as Escherichia coli DNA gyrase inhibitors. Arch Pharm (Weinheim). 2018 Jan;351(1). doi: 10.1002/ardp.201700333. Epub 2017 Dec 14. PMID: 29239018.
  18. Towle TR, Kulkarni CA, Oppegard LM, Williams BP, Picha TA, Hiasa H, Kerns RJ. Design, synthesis, and evaluation of novel N-1 fluoroquinolone derivatives: Probing for binding contact with the active site tyrosine of gyrase. Bioorg Med Chem Lett. 2018 Jun 1;28(10):1903-1910. doi: 10.1016/j.bmcl.2018.03.085. Epub 2018 Mar 30. PMID: 29661533; PMCID: PMC5938125.
  19. Lamut A, Skok Ž, Barančoková M, Gutierrez LJ, Cruz CD, Tammela P, Draskovits G, Szili PÉ, Nyerges Á, Pál C, Molek P, Bratkovič T, Ilaš J, Zidar N, Zega A, Enriz RD, Kikelj D, Tomašič T. Second-generation 4,5,6,7-tetrahydrobenzo[d]thiazoles as novel DNA gyrase inhibitors. Future Med Chem. 2020 Feb;12(4):277-297. doi: 10.4155/fmc-2019-0127. Epub 2020 Feb 11. PMID: 32043377.
  20. Yonezawa M, Takahata M, Banzawa N, Matsubara N, Watanabe Y, Narita H. Analysis of the NH2-terminal 83rd amino acid of Escherichia coli GyrA in quinolone-resistance. Microbiol Immunol. 1995;39(4):243-7. doi: 10.1111/j.1348-0421.1995.tb02196.x. PMID: 7651238.
  21. Barnard FM, Maxwell A. Interaction between DNA gyrase and quinolones: effects of alanine mutations at GyrA subunit residues Ser(83) and Asp(87). Antimicrob Agents Chemother. 2001 Jul;45(7):1994-2000. doi: 10.1128/AAC.45.7.1994-2000.2001. PMID: 11408214; PMCID: PMC90591.
  22. Mehla K, Ramana J. Structural signature of Ser83Leu and Asp87Asn mutations in DNA gyrase from enterotoxigenic Escherichia coli and impact on quinolone resistance. Gene. 2016 Jan 15;576(1 Pt 1):28-35. doi: 10.1016/j.gene.2015.09.063. Epub 2015 Sep 28. PMID: 26424597.
  23. Pourahmad Jaktaji R, Mohiti E. Study of Mutations in the DNA gyrase gyrA Gene of Escherichia coli. Iran J Pharm Res. 2010 Winter;9(1):43-8. PMID: 24363705; PMCID: PMC3869551.
  24. March-Vila E, Pinzi L, Sturm N, Tinivella A, Engkvist O, Chen H, Rastelli G. On the Integration of In Silico Drug Design Methods for Drug Repurposing. Front Pharmacol. 2017 May 23;8:298. doi: 10.3389/fphar.2017.00298. PMID: 28588497; PMCID: PMC5440551.
  25. Mehla K, Ramana J. Structural signature of Ser83Leu and Asp87Asn mutations in DNA gyrase from enterotoxigenic Escherichia coli and impact on quinolone resistance. Gene. 2016 Jan 15;576(1 Pt 1):28-35. doi: 10.1016/j.gene.2015.09.063. Epub 2015 Sep 28. PMID: 26424597.
  26. Fang Y, Lu Y, Zang X, Wu T, Qi X, Pan S, Xu X. 3D-QSAR and docking studies of flavonoids as potent Escherichia coli inhibitors. Sci Rep. 2016 Apr 6;6:23634. doi: 10.1038/srep23634. PMID: 27049530; PMCID: PMC4822154.
  27. Fois B, Skok Ž, Tomašič T, Ilaš J, Zidar N, Zega A, Peterlin Mašič L, Szili P, Draskovits G, Nyerges Á, Pál C, Kikelj D. Dual Escherichia coli DNA Gyrase A and B Inhibitors with Antibacterial Activity. ChemMedChem. 2020 Feb 5;15(3):265-269. doi: 10.1002/cmdc.201900607. Epub 2019 Dec 10. PMID: 31721445.
  28. Singh A, Gupta V. SARS-CoV-2 Therapeutics: How far do we stand from a remedy? Communicated work.

Swift, Reliable, and studious. We aim to cherish the world by publishing precise knowledge.

  • Dimensions
  • zenodo
  • openaire
  • ICI-World
  • icmje
  •  International Scientific Indexing (ISI)
  • Sherpa Romeo
  • ResearchGate
  • Universidad De Lima
  • WorldCat
  • JCU Discovery
  • McGill
  • National University of Singepore Libraries
  • SearchIT
  • Scilit
  • SemantiScholar
  • Base Search
  • VU
  • KB
  • Publons
  • oaji
  • Harvard University
  • sjsu-library
  • UWLSearch
  • FIT
  • CrossRef
  • LUBsearch
  • BIUSante
  • Technical University of Denmark
  • ResearchBIB
  • Google Scholar
  • Microsoft Academic Search



COVID-19 alert