Pyrimidine Oxazolidinone Against Broad Spectrum of Gram Positive Pathogens and Molecular Modeling Studies for Its Interaction with Ribosome

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Review Article *Corresponding author Manoj Kumar Khera, Department of Medicinal Chemistry, Daiichi Sankyo India Pharma Private Limited, Antibacterial Activity of a Village Sarhaul, Sector – 18, Gurgaon – 122 015, India, Tel: 91-9818337315; Fax: 91-124-2397546; Email:

Gram Positive Pathogens and Keywords • Oxazolidinone • Antibacterial Molecular Modeling Studies for • MRSA its Interaction with Ribosome Manoj Kumar Khera1*, Tarun Mathur2, Tarani Kanta Barman2, Ramkumar G2, Manoj Kumar2, Dilip J. Upadhyay2, Tarun Jain1, Om Prakash3, Ian A. Cliffe1, Smita Dube2, and V. Samuel Raj2 1Department of Medicinal Chemistry, Daiichi Sankyo India Pharma Private Limited, India 2Department of Microbiology, Daiichi Sankyo India Pharma Private Limited, India 3Department of Chemistry, Kurushetra University, India

Abstract Oxazolidinones are known to inhibit bacterial protein biosynthesis and act against a wide spectrum of Gram-positive bacteria. Herein, we report a novel investigational oxazolidinone compound 1, which showed potent in vitro activity against Staphylococcus aureus, Staphylococcus epidermidis, Vancomycin resistant enterococci (VRE), Streptococcus pneumoniae, Streptococcus pyogenes and other pathogens. The MIC of compound 1 was 0.125 µg/ml against S.aureus ATCC 25923, whereas that of linezolid was 1 µg/ml. Compound 1 showed faster inhibition of bacterial protein synthesis than Linezolid in S.aureus ATCC 25923. Molecular modeling studies indicated that compound 1 exhibited binding to the ribosome in a similar manner to that of Linezolid and Ranbezolid but with additional interactions from its triazolopyrimidine and thiophene rings which are probably responsible for its stronger in vitro activity.

INTRODUCTION sinusitis, skin infections and bacterial meningitis. The problem is more severe in the hospital setting, where MRSA has emerged. Bacterial infection due to Gram positive bacteria such as methicillin resistant (MRSA), methicillin- Staphylococcus aureus nosocomial pathogen worldwide. The treatment of staphylococcal resistant Staphylococcus epidermidis (MRSE) and vancomycin MRSA was first reported in 1961 and has since become a major resistant enterococci (VRE) have emerged as a major public of resistance to beta-lactams and other antimicrobials, including health problem across the globe. The emergence of antimicrobial infections is becoming difficult due to the increasing emergence resistance among these pathogens has become troublesome for there has been an increase in infections caused by multiple patients and clinicians. In the year 2014, the agency for healthcare reduced susceptibility to glycopeptides [1-6]. In recent years, research & quality reported 23,000 deaths due to MRSA in the pathogens and the situation has become quite alarming with the United States alone. Staphylococci are an important cause of recent emergence of vancomycin-intermediate S.aureus (VISA), infection of the bloodstream, cardiac valves, implanted devices vancomycin resistant enterococci (VRE), etc. and skin and have repercussions on mortality and morbidity. Oxazolidinones are the only new class of synthetic antibiotics Streptococcus pathogens are a major cause of mortality and to be developed in the past 30 years and they act against a wide morbidity associated with bacterial pneumonia, bacteremia, spectrum of primarily Gram-positive bacteria. Oxazolidinones

Cite this article: Khera MK, Mathur T, Barman TK, Ramkumar G, Kumar M, et al. (2017) Antibacterial Activity of a Novel 1,2,4-Triazolo [4,3-A] Pyrimidine Oxazolidinone against Broad Spectrum of Gram Positive Pathogens and Molecular Modeling Studies for its Interaction with Ribosome. JSM Microbiology 5(1): 1034. Khera et al. (2017) Email:

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Central Bringing Excellence in Open Access have a mechanism of action which involves inhibiting the acetylglucosamine were procured either from Perkin Elmer initiation of protein synthesis at a site different from other known (USA) or the Board of Radiation and Isotope Technology (India). protein synthesis inhibitors. These have activity against many antibiotic resistant pathogens, including those cross resistant to Minimum inhibitory concentrations (MICs) The MICs for Linezolid and Compound 1 were performed of action of oxazolidinones have shown no effect on DNA and against Gram-positive facultative and fastidious strains according protein synthesis inhibitors [7]. Early studies on the mechanism to Clinical and Laboratory Standard Institute (CLSI) guidelines (CLSI, 2012). RNA synthesis [8-10]. class for the treatment of a number of infections including Time-kill kinetic studies complicatedLinezolid skin was and the skinfirst structureantibacterial infections drug in caused the oxazolidinone by S. aureus (MRSA and MSSA), S. pyogenes or S. agalactiae; uncomplicated The time-kill kinetic studies were performed as per Hoellman skin and soft tissue infections caused by S. aureus or S.pyogenes; S. aureus hospital acquired pneumonia caused by S. aureus; and community et al. [19]. The ATCC 25923 was exposed to compound acquired pneumonia caused by S.pneumoniae, S. aureus or ml. Time–kill kinetic data were determined from the reduction 1 or Linezolid at concentrations ranging from 0.5µg/ml to 16 µg/ vancomycin-resistant Enterococcus faecium in viable count (Log10cfu/ml) at 2h, 4h and 8h and compared Tedizolid phosphate was developed for the treatment of acute with 0 h. Antibiotics were considered bactericidal at the lowest [11]. Subsequently, bacterial skin and skin structure infections; however, it cannot concentration that reduced the original inoculum by >3 log10 cfu/

10cfu/ml. many investigational oxazolidinones have been reported which Macromolecular synthesis inhibition studies in S. havebe used shown for neutropenica good spectrum patients of activity [12]. Over against a period Gram-positive of time, ml (99.9% killing) and bacteriostatic if <3 log aureus ATCC 25923 The macromolecular biosynthesis inhibition in S. aureus pathogensThe crystal [7,13-16]. structure of Linezolid bound to the 50S ribosomal unit was reported by Duffy et al., from Rib-X pharmaceuticals S.aureus wasATCC grown 25923 in was Muller studied Hinton as describedBroth (MHB) by Olivamedium. et al. Radioactive [20], with observation was the morpholine ring of Linezolid appearing some modifications by Kalia3 et al [10]. The ATCC14 25923 [17]. Along with the identification of key interactions, a significant C-labeled compounds) were added during the early logarithmic phase replacement with a wide variety of other groups was found to (ODprecursors0.3) (1 and μCi/ml after for 5 minutesH-labeled inhibitors and 0.1 μCi/ml were addedfor at their resultnot to in make an improvement significant interactions in antibacterial with activity. the ribosome and its minimum600 inhibitory concentration (MIC), as determined by a In this paper we report the in vitro properties against microdilution method. The macromolecules (DNA, RNA, protein, Staphylococci and Streptococci and mode of action of the fatty acid and cell wall) were precipitated with trichloroacetic investigational oxazolidinone compound 1 (Figure 1) wherein morpholine ring of Linezolid has been replaced with a a wereacid (final dried 5%, overnight wt/vol) at and 37o filtered on glass fibre filters (1.0 μM addition, we report the molecular docking studies used to explain A/B glass multi-well filter plates, Pall Corporation). The plates 3-(thiophen-2-yl)[1,2,4]triazolo[4,3- ]pyrimidine moiety. In the interaction of compound 1 with the ribosome. performed with a scintillationC. Thecounter quantification (Wallac Ltd). of radioactivity was done using OptiPhase safe scintillation fluid and counting MATERIALS AND METHODS Molecular modeling studies for interaction of Bacterial strains and antibiotics compound 1 with ribosome The set of Gram-positive facultative and fastidious ATCC The molecular modeling studies were carried out using strains used in this study are shown in (Table 1,2). The S.aureus (Schrodinger). The crystal structure of the E. coli 50S large Maestro 9.3 molecular modeling software from Schrodinger synthesis inhibition studies. The oxazolidinone compound 1 was ATCC 25923 strain was used for kill kinetics and macromolecule subunit of ribosome (PDB ID 2AW4) [21] was used to build a from commercial sources. The radiolabeled compounds working model based on residues within 30 Å of A2541 [22]. synthesized3H-thymidine, in-house 3H-uridine, [18] 14andC-isoleucine, other antibiotics 14C-acetate, were and procured 3H-N- the crystal structure using the Protein Preparation Wizard in Hydrogen atoms and force field parameters were added to

O N N O O N O N O N H N N H N N CH S 3 F O F O

Linezolid Compound 1

Figure 1 Structures of Linezolid and Compound 1.

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Table 1: In vitro susceptibility of compound 1 against facultative Gram 18 S. agalactiae ATCC 13813 1 0.125 positive pathogens. S. agalactiae 1 0.125 MIC µg/ml 20 S. pneumoniae 1 0.125 S.NO ORGANISMS Linezolid Compound 1 19 ATCC 27956 1 S.aureus 1 0.125 21 S. pneumoniae ATCC 49619 0.5 2 S.aureus 2 0.25 22 S. pneumoniae 0.5 ATCC 25923 406081 erm B 0.06 3 S.aureus 4 0.5 ATCC 13709 Smith 23 S. pneumoniae R 6 1 0.1250.06 4 MRSA ATCC 43300 2 0.25 ATCC 29213 24 S. pneumoniae 0.5 5 1 0.25 6303 25 S. pneumoniae 2 0.125 S.aureus2 (PVL+ve) 2 0.25 3579 erm 0.06 MRSA 562 7 S.aureus +ve) 2 0.25 S. pneumoniae MA994 80 mef erm 0.5 6 8 2 0.25 S. pneumoniae 1199B (Nor pump 2726 1 0.1250.06 S.aureus 1 0.125 R MRSA WCU H29 ATCC 49619 Nov 10 1 0.125 9 ATCC Newman 25904 11 S.aureus 1 Maestro. An active site model was generated using the Receptor MRSA ATCC BAA 39 12 S.aureus 1 0.125 Grid Generation protocol by selecting A2451 as the center of the FDA209P 0.06 grid. The compound 1 was docked into the generated receptor 13 MRSA 252 BAA 1720 1 0.125 DB00026 14 S.epidermidis ATCC 12228 0.5 0.03 generated in this manner were analyzed. 15 1 0.125 grid using Glide docking module [23] and the binding poses 1 RESULTS MRSE ATCC 35983 17 S. epidermidis 0.5 16 MRSE ATCC 35984 0.06 Antimicrobial activity of compound 1 18 E. faecalis 2 0.25 ATCC 14990 0.06 E.faecalis 2 The in vitro results of the testing of compound 1 and linezolid ATCC 29212 20 E.faecalis 2 0.25 against a broad spectrum of pathogens causing skin infection, 19 ATCC 51299(VRE&HLAR) 0.06 21 E.faecium 1 0.125 bacteremia and pneumonia are given in (Tables 1,2). The MICs of ATCC 19433 compound 1 and linezolid against 22 E.faecium 1 0.125 S.aureus S.aureus ATCC 49224 23 E.faecium 1 0.125 6A (VRE) 0.125, 0.25 and 0.25 µg/ml and 1, 4, 2 and 2ATCC µg/ml, 25923, respectively. 24 E.faecium 1 0.125 ATCC 19434 TheATCC MICs 29213, of compound MRSA ATCC 1 43300and linezolid and MRSA against WCU S.pyogenes H29 were 0.125,ATCC 25 E.faecium 1 0.125 06076VRE S.pyogenes ATCC 12344, S.pneumoniae E.coli >8 >8 ATCC 35667 S.pneumoniae 27 E.coli 120 (Acr-ve) 4 >8 19615, ATCC 49619 and 26 7632 ml and 1, 1, 1 and 1 µg/ml, respectively. The detailed MICs of compound 1 and6303 linezolid were 0.125, against 0.125, a broad 0.125 spectrum and 0.125 of other µg/ Table 2: In vitro susceptibility of compound 1 against fastidious Gram strains are given in (Tables 1,2). positive pathogens. Kill kinetics of Compound 1 and Linezold against S. MIC (μg/ml) aureus ORGANISMS Linezolid Compound 1 In time kill study, both compound 1 and linezolid showed 1 S. pyogenes 1 0.125 bacteriostatic effects against S. aureus 2 S. pyogenes 203 C 1 0.125 ATCC 19615 Macromolecular synthesis inhibition 3 S. pyogenes 3814 erm A 0.5 25923 up to 8 h. 4 S. pyogenes 1721erm A 1 0.125 Compound 1 was found to be a potent inhibitor of protein 0.06 synthesis in S.aureus 5 S. pyogenes 2534 erm B 1 0.125 S. pyogenes 0.5 nascent polypeptide chain25923 during as it inhibited protein synthesisthe incorporation (Figure 2).of the The specific effect ofradiolabeled compound precursor 1 was faster [14C] than isoleucine that of linezolidinto the 67 S. pyogenes 2569 erm A 0.5 0.06 8 S. pyogenes 2033 erm B 0.5 2368 erm B 0.06 by compound 1 or linezolid in S. aureus R S. pyogenes 2534 Nov erm B 1 0.1250.06 amount(30min vs.of inhibition 60 min). DNAof cell and wall RNA and synthesislipid synthesis were wasnot observedinhibited 25923. However, a small 109 S. pyogenes ATCC 12344 1 0.125 11 S. salivarius 1 0.125 (Figure 2a and 2b). The macromolecular synthesis inhibition for both compounds at 60 minutes in a non-specific manner 12 S. viridans 2 0.125 ATCC 13419 inhibitor than Linezolid. In another experiment, Linezolid 13 S. mitis 1263 1 inhibiteddata confirmed the protein compound synthesis 1 to be of more S. aureus potent with protein less synthesis potency, 14 S. mutansATCC 49456 4 0.060.25 but stronger protein synthesis inhibition was observed with compound 1 (Figure 2c). Compound 1 inhibited protein synthesis 15 S. salivaries 956 1 0.125 S. sanguis 1061 1 1716 S. viridansSS982 1 0.1250.06 synthesis(approximately inhibition 50% (Figure inhibition) 2c). at 0.25 μg/ml concentration, while 1 μg/ml of Linezolid was needed to show similar protein 659 JSM Microbiology 5(1): 1034 (2017) 3/6 Khera et al. (2017) Email:

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a. b. 60 60

50 50

40 40

30 30 %Inhibition 20 %Inhibition 20

10 10

0 0 NAG NAG Uridine Uridine Isoleucine Isoleucine Thymidine Acetate Thymidine Acetate

10' 30' 60' 10' 30' 60'

Figure 2 Macromolecular synthesis inhibition in S.aureus 1 at a concentration of compound 0.5 µg/ml. ATCC 25923. (a) Profile of compound S. aureus by compound 1 and Linezolid. (b) Profile of Linezolid at a concentration of 2 µg/ml. (c) Protein synthesis inhibition (%) in Molecular interaction of the compound 1 with ribosome of a macromolecular synthesis inhibition assay. As expected from1 was anconfirmed oxazolidinone to act by class the ofsame molecules, unique mechanism both compound by use 1 and linezolid showed in vitro activity against the Gram-positive synthesis, it was important to understand the nature of binding pathogens tested in this study. Compound 1 showed at least a 4- modeSince of compound compound 1 1 to specifically the bacterial inhibited ribosome. bacterial Compound protein 1 to 8- fold more potent inhibition of staphylococci, enterococci and was docked in the crystal structure of the 50S ribosomal unit streptococcus strains than linezolid (Table 1 and 2). The improved of E. coli (Figure 3) with the result that its binding mode was in vitro activity of compound 1 may be attributed to additional interactions (shown by modeling studies) of its thiophene and The oxazolidinone ring forms a stacking interaction with the triazolopyrimidine rings with the ribosome, which are absent in facefound of tothe be uracil similar base to of thatU2504. of LinezolidOther residues and Ranbezolid interacting [10].with linezolid. The in vitro activity of compound 1 is comparable to an the oxazolidinone ring are the sugar of G2505 and the base of oxazolidinone ring and the amide N-H makes a hydrogen bond earlierAlthough compound both Ranbezolid compound [10] from 1 and our laboratory. Linezolid showed interactionG2061. The with amide the side-chain 5’-oxygen of atom compound of G2505. 1 is The folded phenyl over ring the bacteriostatic effect in kill kinetic studies, compound 1 showed proximal to the oxazolidinone ring is stabilized by the bases a more rapid protein synthesis inhibition in S.aureus than A2451 and C2452, while the thiophene ring is stabilized by Van Linezolid. The inhibition of protein synthesis by compound 1 and der Waals interactions with the sugar residues A2451, C2452 and . Additionally, the triazolopyrimidine ring is stabilized by residues A2451, U2584 and U2585. Linezolid are specific oxazolidione class effects, as they both bind U2506 toCONCLUSION the 50s ribosome [14,22,26,27]. DISCUSSION Compound 1 is a potent protein synthesis inhibitor with The oxazolidinones are inhibitors of bacterial protein in vitro activities against a broad spectrum of pathogens and, therefore, has the potential to be developed as an inhibitor of synthesis with a unique mechanism of action [7,24,25]. Compound JSM Microbiology 5(1): 1034 (2017) 4/6 Khera et al. (2017) Email:

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WE. Multidrug-resistant Streptococcus pneumoniae infections: current

5. and future therapeutic options. Drugs. 2007; 67: 2355-2382. et al. Antimicrobial drug use and infection control practices associated withMacKenzie the prevalence FM, Bruce of J, Struelensmethicillin-resistant MJ, Goossens Staphylococcus H, Mollison J, Gouldaureus IM, in

European hospitals. Clin Microbiol Infect. 2007; 13: 269-276. staphylococci: update on the molecular epidemiology and clinical 6. presentation,Widerstrom M, withWistrom a focus J, Sjostedt on StaphylococcusA, Monsen T. Coagulase-negative epidermidis and Staphylococcus saprophyticus 31: 7-20. . Eur J Clin Microbiol Infect Dis. 2012; 7. and in vitro and in vivo Daly JS, Eliopoulos GM, Willey S, Moellering RC. Mechanism of action activities of S-6123, a new oxazolidinone 8. compound.Eustice DC, AntimicrobFeldman PA, Agents Zajac I,Chemother. Slee AM. Mechanism 1988; 32: 1341-1346.of action of DuP 721: inhibition of an early event during initiation of protein synthesis.

Antimicrob Agents Chemother. 1988; 32: 1218-1222. al. In vivo 9. antimicrobialFord CW, Hamel agents, JC, Wilson against DM, Moerman experimental JK, Stapert bacterial D, Yancey infections. RJ, et activities of U-100592 and U-100766, novel oxazolidinone

10. Antimicrob Agents Chemother. 1996; 40: 1508-1513. Mode of action of Ranbezolid against staphylococci and structural modelingKalia V, Miglani studies R, of Purnapatre its interaction KP, with Mathur ribosomes. T, Singhal Antimicrob S, Khan S,Agents et al.

11. Chemother. 2009; 53: 1427-1433. Intern Med. 2003; 138: 135-142. Moellering RC. Linezolid: the first oxazolidinone antimicrobial. Ann 12. Center for Drug Evaluation and Research. Application Number: 205435Orig1s000.

13. Barry AL. In vitro evaluation of DuP 105 and DuP 721, two new Figure 3 Predicted binding mode of compound 1 in the active site oxazolidinone antimicrobial agents. Antimicrob Agents Chemother. of E.coli 50S ribosome sub-unit. Compound 1 is shown as a ball & stick model (carbon atoms in green color) and the ribosome subunit residues are shown as a thin stick model. The nitrogen atom of 14. 1988;Bozdogan 32: 150-152.B, Appelbaum PC. Oxazolidinones: activity, mode of action, the oxazolidinone ring makes a hydrogen bond interaction with the 5’-oxygen atom of G2505 as shown by the yellow dotted line. and mechanism of resistance. Int J Antimicrob Agents. 2004; 23: 113- 15. 119.Eliopoulos GM, Wennersten CB, Gold HS, Moellering RC. In vitro both staphylococcus and streptococcus infections. Additional activities in new oxazolidinone antimicrobial agents against enterococci help in exploring the possibility of taking this compound into . Antimicrob Agents Chemother. 1996; 40: 1745-1747. preclinicalpharmacokinetic development and pharmacodynamic as a potential candidate (PKPD) against studies skin and will H, et al. Synthesis of conformationally constrained analogues of soft tissue infection, pneumonia and bacteremia. 16. Linezolid:Selvakumar structure-activity N, Srinivas D, Khera relationship MK, Kumar (SAR) MS, Mamidi studies RN, on selectedSarnaik ACKNOWLEDGEMENTS 17. novel tricyclic oxazolidinones. J Med Chem. 2002; 45: 3953-3962. al. Crystal structure of the oxazolidinone antibiotic Linezolid bound to Pharma Private Limited is acknowledged. Ippolito JA, Kanyo ZF, Wang D, Franceschi FJ, Moore PB, Steitz TA, et The financial support for research from Daiichi Sankyo India REFERENCES 18. the 50S ribosomal subunit. J Med Chem. 2008; 51: 3353-3356.in vitro activity 1. Chopra I. Antibiotic resistance in staphylococcus aureus: concerns, Khera MK, Cliffe IA, Mathur T, Prakash O. Synthesis and causes and cures. Expert Rev Anti-Infect Ther. 2003; 1: 45-55. of novel 1,2,4-triazolo [4,3-a]pyrimidine oxazolidinone antibacterial agents. Bioorg Med Chem Lett. 2011; 21: 2887-2889. 2. Antipneumococcal and antistaphylococcal activities of ranbezolid In Vitro and In Vivo 19. Hoellman DB, Lin G, Ednie LM, Rattan A, Jacobs MR, Appelbaum PC. Barman TK, Kumar M, Mathur T, Chaira T, Ramkumar G, Kalia V, et al. Antimicrob Agents Chemother. 2003; 47: 1148-1150. Activities of a Bi-Aryl Oxazolidinone, RBx 11760, (RBX 7644), a new oxazolidinone, compared to those of other agents. against Gram-Positive Bacteria. Antimicrob Agents Chemother. 2016; 20. 3. 60: 7134-7145. properties and mode of action of the pyrrothine holomycin. surveillance and preventative measures for methicillin-resistant Oliva B, O’Neill A, Wilson JM, O’Hanlon PJ, Chopra I. Antimicrobial staphylococcusKavanagh KT, Calderon aureus infections LE, Saman in DM, surgical Abusalem patients. SK. TheAntimicrob use of 21. Schuwirth BS, Borovinskaya MA, Hau CW, Zhang W, Vila-Sanjurjo Resist Infect Control. 2014; 3:18. Antimicrob Agents Chemother. 2001; 45: 532-539. Å 4. Van Bambeke F, Reinert RR, Appelbaum PC, Tulkens PM, Peetermans resolution. Science. 2005; 310: 827-834. A, Holton JM, et al. Structures of the bacterial ribosome at 3.5

JSM Microbiology 5(1): 1034 (2017) 5/6 Khera et al. (2017) Email:



Central Bringing Excellence in Open Access

22. 25. Swaney SM, Aoki H, Ganoza MC, Shinabarger DL. The oxazolidinone et al. The site of action of oxazolidinone antibiotics in living bacteria Linezolid inhibits initiation of protein synthesis in bacteria. Leach KL, Swaney SM, Colca JR, McDonald WG, Blinn JR, Thomasco LM,

23. and in human mitochondria. Mol Cell. 2007; 26: 393-402. Antimicrob Agents Chemother. 1998; 42: 3251-3255. al. Glide: A new approach for rapid, accurate docking and scoring. 1. eperezolid binds to the 50S ribosomal subunit and competes with Friesner RA, Banks JL, Murphy RB, Halgren TA, Klicic JJ, Mainz DT, et 26. bindingLin AH, ofMurray chloramphenicol RW, Vidmar and TJ, Marottilincomycin. KR. Antimicrob The oxazolidinone Agents

Method and assessment of docking accuracy. J Med Chem. 2004; 47: 24. 1739-1749.Livermore DM, Warner M, Mushtaq S, North S, Woodford N. In vitro 27. Chemother. 1997; 41: 2127-2131. magnetic resonance study of oxazolidinone binding to bacterial and -susceptible staphylococci and enterococci. Antimicrob Agents Zhou CC, Swaney SM, Shinabarger DL, Stockman BJ. 1H nuclear activityChemother. of the 2007; oxazolidinone 51: 1112-1114. RWJ-416457 against linezolid -resistant ribosome. Antimicrob Agents Chemother. 2002; 46: 625-629.

Cite this article Khera MK, Mathur T, Barman TK, Ramkumar G, Kumar M, et al. (2017) Antibacterial Activity of a Novel 1,2,4-Triazolo [4,3-A] Pyrimidine Oxazolidinone against Broad Spectrum of Gram Positive Pathogens and Molecular Modeling Studies for its Interaction with Ribosome. JSM Microbiology 5(1): 1034.

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