Breakthrough In Identifying Molecular Target and Mode of Action of Fidaxomicin

Breakthrough In Identifying Molecular Target and Mode of Action of Fidaxomicin

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Highlights:
  • Scientists delineate mechanism of action of fidaxomicin a potent antibacterial drug approved for treatment of CDC "urgent threat" Clostridium difficile, a bacterial pathogen that causes severe inflammation of the colon with diarrhea.
  • The low solubility and low systemic bioavailability of fidaxomicin however, limits its use in other serious infections such as tuberculosis, methicillin-resistant Staphylococcus aureus (MRSA), vancomycin-resistant Staphylococcus aureus (VRSA).
  • Knowledge of fidaxomicin' s mode of inhibitory action on bacterial RNA polymerase (an enzyme needed for bacterial RNA synthesis) will help design newer derivatives of the drug with improved efficacy and wider spectrum of antibacterial activity.
Mechanism and site of action of fidaxomicin (brand name dificid), a potent antibiotic that was approved in 2011 for Clostridium difficile (an intestinal pathogen) infection has now been defined by a team of Rutgers University in collaboration with international scientists.
Breakthrough In Identifying Molecular Target and Mode of Action of Fidaxomicin

The findings of the study were based on cryo-electron microscopy (cryo-EM) and single molecule spectroscopy analyses that reveals how fidaxomicin binds to and inhibits bacterial RNA polymerase  appear in the journal Molecular Cell today.

Details of the Study

  • The team analyzed cryo-electron microscope structure of fidaxomicin binding to Mycobacterium tuberculosis RNA polymerase at 3.5 Å resolution
  • Fidaxomicin was found to bind toa part of RNA polymerase (the RNA polymerase clamp)
  • The clamp must swing open to enable the RNA polymerase to bind to DNA; it then swings shut to allow RNA polymerase to latch firmly onto the DNA
  • The analysis further confirms that the fidaxomicin holds the RNA polymerase "clamp" in the open position, preventing its closure
  • This study, thus shows that fidaxomicin inhibits bacterial RNA polymerase by binding at a different site and has a different mechanism of action different from rifamycins, another group of antibacterial drugs that targets RNA polymerase
  • The above finding explains why fidaxomicin can kill bacteria resistant to rifamycins and also why fidaxomicin has additive effect when combined with rifamycins
  • Based on the structural analysis of fidaxomicin binding to its target, the scientists found portions of fidaxomicin that are not critical for binding and can therefore be modified to producer newer derivatives with improved properties
  • The results of the study will thus help design of new, improved fidaxomicin derivatives with greater antibacterial potency, better solubility, and systemic bioavailability
  • In fact the team has developed methods to allow selective attachment of new chemical groups at these "non-critical" fidaxomicin sites, that can improve efficacy, solubility, or systemic bioavailability
"The results set the stage for development of improved fidaxomicin derivatives, particularly improved fidaxomicin derivatives having the solubility and systemic bioavailability needed for treatment of systemic infections, such as MRSA and tuberculosis " said Ebright, Board of Governors Professor of Chemistry and Chemical Biology and Laboratory Director at the Waksman Institute of Microbiology at Rutgers, who led the research.

Fidaxomicin In Clostridium Difficile Infection

Fidaxomicin is the first narrow spectrum macrocyclic lactone antibiotic with inhibitory activity against C difficileand was approved in 2011. Recent studies suggest that Clostridium difficile has overtaken methicillin-resistant Staphylococcus aureus as the leading cause of hospital acquired infections. Treatment with Fidaxomicin has been found to be associated with fewer rate of recurrent Clostridium difficile infections when compared with vancomycin. It has also been found to be well tolerated and relatively safe in studies.

References:
  1. Wei Lin, Kalyan Das, David Degen, Abhishek Mazumder, Diego Duchi, Dongye Wang, Yon W. Ebright, Richard Y. Ebright, Elena Sineva, Matthew Gigliotti, Aashish Srivastava, Sukhendu Mandal, Yi Jiang, Yu Liu, Ruiheng Yin, Zhening Zhang, Edward T. Eng, Dennis Thomas, Stefano Donadio, Haibo Zhang, Changsheng Zhang, Achillefs N. Kapanidis, Richard H. Ebright. "Structural Basis of Transcription Inhibition by Fidaxomicin (Lipiarmycin A3)." Molecular Cell, (2018); DOI: 10.1016/j.molcel.2018.02.026
Source: Medindia
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