1. Academic Validation
  2. A Trimethoprim Conjugate of Thiomaltose Has Enhanced Antibacterial Efficacy In Vivo

A Trimethoprim Conjugate of Thiomaltose Has Enhanced Antibacterial Efficacy In Vivo

  • Bioconjug Chem. 2018 May 16;29(5):1729-1735. doi: 10.1021/acs.bioconjchem.8b00177.
Xiaojian Wang 1 Clarissa A Borges Xinghai Ning Mohammad Rafi Jingtuo Zhang Bora Park Kiyoko Takemiya 2 Carlo Lo Sterzo W Robert Taylor 2 3 4 Lee Riley Niren Murthy
Affiliations

Affiliations

  • 1 Institute of Advanced Synthesis, School of Chemistry and Molecular Engineering, Jiangsu National Synergetic Innovation Center for Advanced Materials , Nanjing Tech University , Nanjing 211816 , China.
  • 2 Emory University School of Medicine , Department of Medicine, Division of Cardiology , Atlanta , Georgia 30322 , United States.
  • 3 Georgia Institute of Technology , Department of Biomedical Engineering , Atlanta , Georgia 30332 , United States.
  • 4 Atlanta Veterans Affairs Medical Center , Cardiology Division , Atlanta , Georgia 30033 , United States.
Abstract

Trimethoprim is one of the most widely used Antibiotics in the world. However, its efficacy is frequently limited by its poor water solubility and dose limiting toxicity. Prodrug strategies based on conjugation of oligosaccharides to trimethoprim have great potential for increasing the solubility of trimethoprim and lowering its toxicity, but they have been challenging to develop due to the sensitivity of trimethoprim to chemical modifications, and the rapid degradation of oligosaccharides in serum. In this report, we present a trimethoprim conjugate of maltodextrin termed TM-TMP, which increased the water solubility of trimethoprim by over 100 times, was stable to serum enzymes, and was active against urinary tract infections in mice. TM-TMP is composed of thiomaltose conjugated to trimethoprim, via a self-immolative disulfide linkage, and releases 4'-OH-trimethoprim (TMP-OH) after disulfide cleavage, which is a known metabolic product of trimethoprim and is as potent as trimethoprim. TM-TMP also contains a new maltodextrin targeting ligand composed of thiomaltose, which is stable to hydrolysis by serum Amylases and therefore has the metabolic stability needed for in vivo use. TM-TMP has the potential to significantly improve the treatment of a wide number of infections given its high water solubility and the widespread use of trimethoprim.

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