前药TR-701的抗菌部分TR-700对耐利奈唑胺菌株的体外活性。
In vitro activity of TR-700, the antibacterial moiety of the prodrug TR-701, against linezolid-resistant strains.
作者信息
Shaw K J, Poppe S, Schaadt R, Brown-Driver V, Finn J, Pillar C M, Shinabarger D, Zurenko G
机构信息
Trius Therapeutics, Inc., 6310 Nancy Ridge Drive, Suite 105, San Diego, CA 92121, USA.
出版信息
Antimicrob Agents Chemother. 2008 Dec;52(12):4442-7. doi: 10.1128/AAC.00859-08. Epub 2008 Oct 6.
Abstract
TR-701 is the orally active prodrug of TR-700, a novel oxazolidinone that demonstrates four- to eightfold-greater activity than linezolid (LZD) against Staphylococcus and Enterococcus spp. In this study evaluating the in vitro sensitivity of LZD-resistant isolates, TR-700 demonstrated 8- to 16-fold-greater potency than LZD against all strains tested, including methicillin-resistant Staphylococcus aureus (MRSA), strains of MRSA carrying the mobile cfr methyltransferase gene, and vancomycin-resistant enterococci. The MIC(90) for TR-700 against LZD-resistant S. aureus was 2 microg/ml, demonstrating the utility of TR-700 against LZD-resistant strains. A model of TR-700 binding to 23S rRNA suggests that the increased potency of TR-700 is due to additional target site interactions and that TR-700 binding is less reliant on target residues associated with resistance to LZD.
摘要
TR - 701是TR - 700的口服活性前药，TR - 700是一种新型恶唑烷酮，对葡萄球菌和肠球菌的活性比对利奈唑胺（LZD）高4至8倍。在这项评估LZD耐药菌株体外敏感性的研究中，TR - 700对所有测试菌株，包括耐甲氧西林金黄色葡萄球菌（MRSA）、携带移动cfr甲基转移酶基因的MRSA菌株和耐万古霉素肠球菌，显示出比利奈唑胺高8至16倍的效力。TR - 700对LZD耐药金黄色葡萄球菌的MIC（90）为2微克/毫升，表明TR - 700对LZD耐药菌株有效。TR - 700与23S rRNA结合的模型表明，TR - 700效力增加是由于额外的靶位点相互作用，并且TR - 700结合较少依赖于与LZD耐药相关的靶残基。
相似文献
1
In vitro activity of TR-700, the antibacterial moiety of the prodrug TR-701, against linezolid-resistant strains.
Antimicrob Agents Chemother. 2008 Dec;52(12):4442-7. doi: 10.1128/AAC.00859-08. Epub 2008 Oct 6.
2
Novel ribosomal mutations in Staphylococcus aureus strains identified through selection with the oxazolidinones linezolid and torezolid (TR-700).
Antimicrob Agents Chemother. 2009 Dec;53(12):5265-74. doi: 10.1128/AAC.00871-09. Epub 2009 Sep 14.
3
Activity of oxazolidinone TR-700 against linezolid-susceptible and -resistant staphylococci and enterococci.
J Antimicrob Chemother. 2009 Apr;63(4):713-5. doi: 10.1093/jac/dkp002. Epub 2009 Jan 22.
4
Zyvox Annual Appraisal of Potency and Spectrum program: linezolid surveillance program results for 2008.
Diagn Microbiol Infect Dis. 2009 Dec;65(4):404-13. doi: 10.1016/j.diagmicrobio.2009.10.001.
5
Structure-activity relationships of diverse oxazolidinones for linezolid-resistant Staphylococcus aureus strains possessing the cfr methyltransferase gene or ribosomal mutations.
Antimicrob Agents Chemother. 2010 Dec;54(12):5337-43. doi: 10.1128/AAC.00663-10. Epub 2010 Sep 13.
6
AM-7359--a novel oxazolidinone with low resistance potential and potent activity against drug resistant pathogens.
J Chemother. 2007 Jun;19(3):249-55. doi: 10.1179/joc.2007.19.3.249.
7
Telavancin demonstrates activity against methicillin-resistant Staphylococcus aureus isolates with reduced susceptibility to vancomycin, daptomycin, and linezolid in broth microdilution MIC and one-compartment pharmacokinetic/pharmacodynamic models.
Antimicrob Agents Chemother. 2015 Sep;59(9):5529-34. doi: 10.1128/AAC.00773-15. Epub 2015 Jun 29.
8
Comparative pharmacodynamics of the new oxazolidinone tedizolid phosphate and linezolid in a neutropenic murine Staphylococcus aureus pneumonia model.
Antimicrob Agents Chemother. 2012 Nov;56(11):5916-22. doi: 10.1128/AAC.01303-12. Epub 2012 Sep 10.
9
In vitro activity of retapamulin against linezolid and methicillin-resistant Staphylococcus aureus isolates.
Rev Esp Quimioter. 2011 Sep;24(3):127-30.
10
Comparative activities of TR-700 (torezolid) against staphylococcal blood isolates collected in Spain.
Antimicrob Agents Chemother. 2010 May;54(5):2212-5. doi: 10.1128/AAC.01653-09. Epub 2010 Feb 22.
引用本文的文献
1
Advances and prospects for treatment strategies of drug-resistant tuberculosis: a review.
GMS Hyg Infect Control. 2025 Jun 26;20:Doc33. doi: 10.3205/dgkh000562. eCollection 2025.
2
Resistance mechanisms and tedizolid susceptibility in clinical isolates of linezolid-resistant bacteria in Japan.
JAC Antimicrob Resist. 2025 Jun 3;7(3):dlaf097. doi: 10.1093/jacamr/dlaf097. eCollection 2025 Jun.
3
Deciphering linezolid-induced hematologic toxicity: Targeting TOP2A and TOP2B via its primary metabolite PNU142586.
Sci Adv. 2025 May 30;11(22):eadt5833. doi: 10.1126/sciadv.adt5833. Epub 2025 May 28.
4
Comparative In Vitro Drug Susceptibility Study of Five Oxazolidinones Against in Hainan, China.
Pathogens. 2025 Feb 24;14(3):218. doi: 10.3390/pathogens14030218.
5
Oxazolidinone antibiotics impair megakaryocyte differentiation from hematopoietic progenitor cells and their maturation into platelets.
Antimicrob Agents Chemother. 2024 Oct 8;68(10):e0053324. doi: 10.1128/aac.00533-24. Epub 2024 Sep 19.
6
Design, synthesis, and exploration of antibacterial activity of 6-1,2-oxazin-6-ones.
RSC Adv. 2024 Jul 29;14(33):23828-23839. doi: 10.1039/d4ra04220d. eCollection 2024 Jul 26.
7
New Oxazolidinones for Tuberculosis: Are Novel Treatments on the Horizon?
Pharmaceutics. 2024 Jun 17;16(6):818. doi: 10.3390/pharmaceutics16060818.
8
Differences in oxazolidinone resistance mechanisms and small colony variants emergence of induced in an resistance development model.
Emerg Microbes Infect. 2024 Dec;13(1):2292077. doi: 10.1080/22221751.2023.2292077. Epub 2024 Feb 6.
9
Design and Synthesis of Novel Antimicrobial Agents.
Antibiotics (Basel). 2023 Mar 22;12(3):628. doi: 10.3390/antibiotics12030628.
10
Antimicrobial Susceptibility Testing for Enterococci.
J Clin Microbiol. 2022 Sep 21;60(9):e0084321. doi: 10.1128/jcm.00843-21. Epub 2022 Jun 13.
本文引用的文献
1
Crystal structure of the oxazolidinone antibiotic linezolid bound to the 50S ribosomal subunit.
J Med Chem. 2008 Jun 26;51(12):3353-6. doi: 10.1021/jm800379d.
2
First report of cfr-mediated resistance to linezolid in human staphylococcal clinical isolates recovered in the United States.
Antimicrob Agents Chemother. 2008 Jun;52(6):2244-6. doi: 10.1128/AAC.00231-08. Epub 2008 Apr 7.
3
Linezolid resistance in Staphylococcus aureus: gene dosage effect, stability, fitness costs, and cross-resistances.
Antimicrob Agents Chemother. 2008 Apr;52(4):1570-2. doi: 10.1128/AAC.01098-07. Epub 2008 Jan 22.
4
LEADER surveillance program results for 2006: an activity and spectrum analysis of linezolid using clinical isolates from the United States (50 medical centers).
Diagn Microbiol Infect Dis. 2007 Nov;59(3):309-17. doi: 10.1016/j.diagmicrobio.2007.06.004. Epub 2007 Aug 27.
5
Persistence of rRNA operon mutated copies and rapid re-emergence of linezolid resistance in Staphylococcus aureus.
J Antimicrob Chemother. 2007 Sep;60(3):649-51. doi: 10.1093/jac/dkm246. Epub 2007 Jul 10.
6
Acquisition of a natural resistance gene renders a clinical strain of methicillin-resistant Staphylococcus aureus resistant to the synthetic antibiotic linezolid.
Mol Microbiol. 2007 Jun;64(6):1506-14. doi: 10.1111/j.1365-2958.2007.05744.x.
7
The site of action of oxazolidinone antibiotics in living bacteria and in human mitochondria.
Mol Cell. 2007 May 11;26(3):393-402. doi: 10.1016/j.molcel.2007.04.005.
8
Dose dependence of emergence of resistance to linezolid in Enterococcus faecalis in vivo.
J Infect Dis. 2007 May 15;195(10):1480-8. doi: 10.1086/513876. Epub 2007 Apr 3.
9
In vitro activities of DA-7157 and DA-7218 against Mycobacterium tuberculosis and Nocardia brasiliensis.
Antimicrob Agents Chemother. 2006 Sep;50(9):3170-2. doi: 10.1128/AAC.00571-06.
10
The Cfr rRNA methyltransferase confers resistance to Phenicols, Lincosamides, Oxazolidinones, Pleuromutilins, and Streptogramin A antibiotics.
Antimicrob Agents Chemother. 2006 Jul;50(7):2500-5. doi: 10.1128/AAC.00131-06.
Zotero 插件