Myxopyronin
Encyclopedia
Myxopyronin is an alpha-pyrone
antibiotic
, the first in a new class of inhibitors of bacterial RNA polymerase
(RNAP) that target switch 1 and switch 2 of the RNAP "switch region." Rifamycin
antibacterial agents, which are first-line treatments for tuberculosis
, and lipiarmycin (fidaxomicin, Dificid) also target RNAP, but target different sites in RNAP. Myxopyronin does not have cross-resistance
with rifamycins and lipiarmycin. Myxopyronin may be useful to address the growing problem of drug resistance
in tuberculosis. It also may be useful in treatment of methicillin-resistant Staphylococcus aureus
(MRSA). It is in pre-clinical development
and has not yet started clinical trial
s.
Myxopyronin was first isolated in 1983 from a soil bacterium by Rolf Jansen and Herbert Irschik. A total synthesis of myxopyronin was first reported in 1998 by James S. Panek and co-workers. The target, the mechanism of action, and the structure of the complex of RNAP with myxopyronin were first reported in 2008 by Richard H. Ebright
and co-workers. Novel analogs of myxopyronin have been synthesized at Anadys Pharmaceuticals (San Diego, CA) and at Rutgers University (Piscataway, NJ). Terence I. Moy and co-workers at Cubist Pharmaceuticals (Lexington, MA) have stated that, based on high resistance rate and high serum protein binding (comparable to rifamycins and lipiarmycin), the unmodified natural product myxopyronin B is not a viable starting point for antibiotic development.
Pyrone
Pyrones or pyranones are a class of cyclic chemical compounds. They contain an unsaturated six membered ring containing one oxygen atom and a ketone functional group. There are two isomers denoted as 2-pyrone and 4-pyrone. The 2-pyrone structure is found in nature as part of the coumarin ring...
antibiotic
Antibiotic
An antibacterial is a compound or substance that kills or slows down the growth of bacteria.The term is often used synonymously with the term antibiotic; today, however, with increased knowledge of the causative agents of various infectious diseases, antibiotic has come to denote a broader range of...
, the first in a new class of inhibitors of bacterial RNA polymerase
RNA polymerase
RNA polymerase is an enzyme that produces RNA. In cells, RNAP is needed for constructing RNA chains from DNA genes as templates, a process called transcription. RNA polymerase enzymes are essential to life and are found in all organisms and many viruses...
(RNAP) that target switch 1 and switch 2 of the RNAP "switch region." Rifamycin
Rifamycin
The rifamycins are a group of antibiotics that are synthesized either naturally by the bacterium Amycolatopsis mediterranei or artificially. They are a subclass of the larger family Ansamycin...
antibacterial agents, which are first-line treatments for tuberculosis
Tuberculosis
Tuberculosis, MTB, or TB is a common, and in many cases lethal, infectious disease caused by various strains of mycobacteria, usually Mycobacterium tuberculosis. Tuberculosis usually attacks the lungs but can also affect other parts of the body...
, and lipiarmycin (fidaxomicin, Dificid) also target RNAP, but target different sites in RNAP. Myxopyronin does not have cross-resistance
Cross-resistance
Cross-resistance is the tolerance to a usually toxic substance as a result of exposure to a similarly acting substance. It is a phenomenon affecting e.g. pesticides and antibiotics. As an example rifabutin and rifampin cross react in the treatment of tuberculosis. This sort of resistance is also...
with rifamycins and lipiarmycin. Myxopyronin may be useful to address the growing problem of drug resistance
Drug resistance
Drug resistance is the reduction in effectiveness of a drug such as an antimicrobial or an antineoplastic in curing a disease or condition. When the drug is not intended to kill or inhibit a pathogen, then the term is equivalent to dosage failure or drug tolerance. More commonly, the term is used...
in tuberculosis. It also may be useful in treatment of methicillin-resistant Staphylococcus aureus
Methicillin-resistant Staphylococcus aureus
Methicillin-resistant Staphylococcus aureus is a bacterium responsible for several difficult-to-treat infections in humans. It is also called multidrug-resistant Staphylococcus aureus and oxacillin-resistant Staphylococcus aureus...
(MRSA). It is in pre-clinical development
Pre-clinical development
In drug development, pre-clinical development is a stage of research that begins before clinical trials can begin, and during which important feasibility, iterative testing and drug safety data is collected....
and has not yet started clinical trial
Clinical trial
Clinical trials are a set of procedures in medical research and drug development that are conducted to allow safety and efficacy data to be collected for health interventions...
s.
Myxopyronin was first isolated in 1983 from a soil bacterium by Rolf Jansen and Herbert Irschik. A total synthesis of myxopyronin was first reported in 1998 by James S. Panek and co-workers. The target, the mechanism of action, and the structure of the complex of RNAP with myxopyronin were first reported in 2008 by Richard H. Ebright
Richard H. Ebright
Richard High Ebright is an American molecular biologist. He is Professor II of Chemistry and Chemical Biology at Rutgers University, Laboratory Director at the Waksman Institute of Microbiology, and an Investigator of the Howard Hughes Medical Institute.Ebright received an A.B. summa cum laude in...
and co-workers. Novel analogs of myxopyronin have been synthesized at Anadys Pharmaceuticals (San Diego, CA) and at Rutgers University (Piscataway, NJ). Terence I. Moy and co-workers at Cubist Pharmaceuticals (Lexington, MA) have stated that, based on high resistance rate and high serum protein binding (comparable to rifamycins and lipiarmycin), the unmodified natural product myxopyronin B is not a viable starting point for antibiotic development.