Methicillin Resistance Staphylococcus aureus Treatment by Targeting Ribosomal RNA using modified linezolid: A Structure Based CADD Analysis Approach

  • Lokesh Ravi VIT University
  • Bhakyashree Krishnamoorthy VIT UNIVERSITY
  • Krishana Kannabiran VIT University
Keywords: Methicillin resistance Staphylococcus aureus, Linezolid, AutoDock vina, Ribosomal RNA docking, ADMET analysis.

Abstract

Microbial drug resistance is increasing worldwide and currently it is considered as great threat to human health and wellbeing. Superbugs methicillin resistance Staphylococcus aureus (MRSA) and vancomycin- resistant Enterococci (VRE) are developing resistance to most of the drugs. Linezolid is often used as choice of the drug to control MRSA and VRE infections. Long term use of linezolid has led to peripheral neurotoxicity and kidney toxicity. An attempt was made to modify the antibiotic linezolid and to study its interaction with 23S rRNA. Three modified linezolid ligands (MLL) were chosen based on drug likeness score. AutoDock vina was used to perform the docking analysis between 23S rRNA and the MLLs. ADMET properties of the linezolid and the modified ligand molecules were analyzed using admetSAR online server. Among the three MLLs, MLL-1 interacted with 23S rRNA and showed the least binding energy of -8.8 Kcal/mol with 3 hydrogen bonds. MLL-1 demonstrated no mutagenicity, tumorigenicity, irritability and reproductive effects. The AutoDock vina analysis of MLL-1 with 23S rRNA revealed that, better drug-likeness, increased ADMET property and high affinity towards 23S rRNA suggesting MLL-1 is a better drug of choice for the treatment MRSA infections.

References

Green, B.N., Johnson, C.D., Egan, J.T., Rosenth, M., Griffith, E.A., Evans, M.W., 2012. Methicillin-resistant Staphylococcus aureus: an overview for manual therapist. Journal of Chiropractic Medicine 1, 64–76.
van de Waterbeemd, H., Gifford, E., 2003. ADMET in silico modelling: towards prediction paradise? Nature Reviews Drug Discovery 2,192-204.
Haq, M.E., Shahriar, M., Haq, A., Gomes, B.C., Hossain, M.M., Razzak, M.A., et al., 2011. Prevalence of β-lactamase-producing and non-producing methicillin resistant Staphylococcus aureus in clinical samples in Bangladesh. Journal of Microbiology and Antimicrobial agents 3,112-118.
Lambert, T., 2012. Antibiotics that affect the ribosome. Rev. Sci. Tech, Off, Int. Epiz. 31, 57-64.
Livermore, D.M., 2000. Antibiotic resistance in staphylococci. International Journal of Antimicrobial Agents 16, S3–S10.
Mainous, A.G., Hueston, WJ., Everett, CJ., Diaz, VA., 2006. Nasal Carriage of Staphylococcus aureus and Methicillin-Resistant S aureus in the United States, 2001-2002. Annals of Family Medicine 4,132-137.
Mueller, F., Sommer, I., Baranov, P., Matadeen, R., Stoldt, M., Wöhnert, J., Görlach, M., van Heel, M., Brimacombe, R., 2000. The 3D arrangement of the 23 S and 5 S rRNA in the Escherichia coli 50 S ribosomal subunit based on a cryo-electron microscopic reconstruction at 7.5 A resolution. Journal of Molecular Biology 298, 35–59.
Pantosti, A., Sanchini, A., Monaco, M., 2007. Mechanisms of antibioticresistance in Staphylococcus aureus. Future Microbiology 2, 323–334
Rossolini, G.M., Arena, F., Pollini, S., 2014. Novel infectious diseases and emerging gram-positive multiresistant pathogens in hospital and community acquired infections. In Antimicrobials; Marinelli, F., Genilloud, O., Eds.; Springer Verlag: Berlin Heidelberg, Germany.
Sliwoski, G., Kothiwale, S., Meiler, J., Lowe, E.W., 2014. Computational methods in drug discovery. Pharmacology Reviews 66, 334–395.
Wilson, D.N., 2014. Ribosome-targeting antibiotics and mechanisms of bacterial resistance. Nature Reviews Microbiology 12: 35–48.
Published
2017-02-27
Section
Articles