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Myxopyronins (Myx) are a group of alpha-pyrone antibiotics, which are inhibitors of bacterial RNA polymerase (RNAP). [1] [2] They target switch 1 and switch 2 of the RNAP "switch region". [3] Rifamycins and fidaxomicin also target RNAP, but target different sites in RNAP. Myxopyronins do not have cross-resistance with any other drugs so myxopyronins may be useful to address the growing problem of drug resistance in tuberculosis. [4] They also may be useful in treatment of methicillin-resistant Staphylococcus aureus (MRSA). They are in pre-clinical development and has not yet started clinical trials.
Myxopyronin was first isolated in 1983 from a soil bacterium by Werner Kohl and Herbert Irschik at the Helmholtz Centre for Infection Research (former GBF). [1] A total synthesis of myxopyronin was first reported in 1998 by James S. Panek and co-workers. [5]
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. [6] [7] Synthetic analogs of the natural myxopyronins have been synthesized at Anadys Pharmaceuticals and at Rutgers University. [8] [9]
Terence I. Moy and co-workers at Cubist Pharmaceuticals 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. [10]
Transcription is the process of copying a segment of DNA into RNA. The segments of DNA transcribed into RNA molecules that can encode proteins are said to produce messenger RNA (mRNA). Other segments of DNA are copied into RNA molecules called non-coding RNAs (ncRNAs). mRNA comprises only 1–3% of total RNA samples. Less than 2% of the human genome can be transcribed into mRNA, while at least 80% of mammalian genomic DNA can be actively transcribed, with the majority of this 80% considered to be ncRNA.
In molecular biology, RNA polymerase, or more specifically DNA-directed/dependent RNA polymerase (DdRP), is an enzyme that catalyzes the chemical reactions that synthesize RNA from a DNA template.
A sigma factor is a protein needed for initiation of transcription in bacteria. It is a bacterial transcription initiation factor that enables specific binding of RNA polymerase (RNAP) to gene promoters. It is homologous to archaeal transcription factor B and to eukaryotic factor TFIIB. The specific sigma factor used to initiate transcription of a given gene will vary, depending on the gene and on the environmental signals needed to initiate transcription of that gene. Selection of promoters by RNA polymerase is dependent on the sigma factor that associates with it. They are also found in plant chloroplasts as a part of the bacteria-like plastid-encoded polymerase (PEP).
The preinitiation complex is a complex of approximately 100 proteins that is necessary for the transcription of protein-coding genes in eukaryotes and archaea. The preinitiation complex positions RNA polymerase II at gene transcription start sites, denatures the DNA, and positions the DNA in the RNA polymerase II active site for transcription.
The rifamycins are a group of antibiotics that are synthesized either naturally by the bacterium Amycolatopsis rifamycinica or artificially. They are a subclass of the larger family of ansamycins. Rifamycins are particularly effective against mycobacteria, and are therefore used to treat tuberculosis, leprosy, and mycobacterium avium complex (MAC) infections.
Rifampicin, also known as rifampin, is an ansamycin antibiotic used to treat several types of bacterial infections, including tuberculosis (TB), Mycobacterium avium complex, leprosy, and Legionnaires’ disease. It is almost always used together with other antibiotics with two notable exceptions: when given as a "preferred treatment that is strongly recommended" for latent TB infection; and when used as post-exposure prophylaxis to prevent Haemophilus influenzae type b and meningococcal disease in people who have been exposed to those bacteria. Before treating a person for a long period of time, measurements of liver enzymes and blood counts are recommended. Rifampicin may be given either by mouth or intravenously.
RNA polymerase II is a multiprotein complex that transcribes DNA into precursors of messenger RNA (mRNA) and most small nuclear RNA (snRNA) and microRNA. It is one of the three RNAP enzymes found in the nucleus of eukaryotic cells. A 550 kDa complex of 12 subunits, RNAP II is the most studied type of RNA polymerase. A wide range of transcription factors are required for it to bind to upstream gene promoters and begin transcription.
General transcription factors (GTFs), also known as basal transcriptional factors, are a class of protein transcription factors that bind to specific sites (promoter) on DNA to activate transcription of genetic information from DNA to messenger RNA. GTFs, RNA polymerase, and the mediator constitute the basic transcriptional apparatus that first bind to the promoter, then start transcription. GTFs are also intimately involved in the process of gene regulation, and most are required for life.
The rpoB gene encodes the β subunit of bacterial RNA polymerase and the homologous plastid-encoded RNA polymerase (PEP). It codes for 1342 amino acids in E. coli, making it the second-largest polypeptide in the bacterial cell. It is targeted by the rifamycin family of antibacterials, such as rifampin. Mutations in rpoB that confer resistance to rifamycins do so by altering the protein's drug-binding residues, thereby reducing affinity for these antibiotics.
Multicopy single-stranded DNA (msDNA) is a type of extrachromosomal satellite DNA that consists of a single-stranded DNA molecule covalently linked via a 2'-5'phosphodiester bond to an internal guanosine of an RNA molecule. The resultant DNA/RNA chimera possesses two stem-loops joined by a branch similar to the branches found in RNA splicing intermediates. The coding region for msDNA, called a "retron", also encodes a type of reverse transcriptase, which is essential for msDNA synthesis.
T7 RNA Polymerase is an RNA polymerase from the T7 bacteriophage that catalyzes the formation of RNA from DNA in the 5'→ 3' direction.
Intrinsic, or rho-independent termination, is a process in prokaryotes to signal the end of transcription and release the newly constructed RNA molecule. In prokaryotes such as E. coli, transcription is terminated either by a rho-dependent process or rho-independent process. In the Rho-dependent process, the rho-protein locates and binds the signal sequence in the mRNA and signals for cleavage. Contrarily, intrinsic termination does not require a special protein to signal for termination and is controlled by the specific sequences of RNA. When the termination process begins, the transcribed mRNA forms a stable secondary structure hairpin loop, also known as a Stem-loop. This RNA hairpin is followed by multiple uracil nucleotides. The bonds between uracil and adenine are very weak. A protein bound to RNA polymerase (nusA) binds to the stem-loop structure tightly enough to cause the polymerase to temporarily stall. This pausing of the polymerase coincides with transcription of the poly-uracil sequence. The weak adenine-uracil bonds lower the energy of destabilization for the RNA-DNA duplex, allowing it to unwind and dissociate from the RNA polymerase. Overall, the modified RNA structure is what terminates transcription.
Streptolydigin (Stl) is an antibiotic that works by inhibiting nucleic acid chain elongation by binding to RNA polymerase, thus inhibiting RNA synthesis inside a cell. Streptolydigin inhibits bacterial RNA polymerase, but not eukaryotic RNA polymerase. It has antibacterial activity against a number of Gram positive bacteria.
(p)ppGpp, guanosine pentaphosphate and tetraphosphate, also known as the "magic spot" nucleotides, are alarmones involved in the stringent response in bacteria that cause the inhibition of RNA synthesis when there is a shortage of amino acids. This inhibition by (p)ppGpp decreases translation in the cell, conserving amino acids present. Furthermore, ppGpp and pppGpp cause the up-regulation of many other genes involved in stress response such as the genes for amino acid uptake and biosynthesis.
A protein synthesis inhibitor is a compound that stops or slows the growth or proliferation of cells by disrupting the processes that lead directly to the generation of new proteins.
RNA polymerase IV is an enzyme that synthesizes small interfering RNA (siRNA) in plants, which silence gene expression. RNAP IV belongs to a family of enzymes that catalyze the process of transcription known as RNA Polymerases, which synthesize RNA from DNA templates. Discovered via phylogenetic studies of land plants, genes of RNAP IV are thought to have resulted from multistep evolution processes that occurred in RNA Polymerase II phylogenies. Such an evolutionary pathway is supported by the fact that RNAP IV is composed of 12 protein subunits that are either similar or identical to RNA polymerase II, and is specific to plant genomes. Via its synthesis of siRNA, RNAP IV is involved in regulation of heterochromatin formation in a process known as RNA directed DNA Methylation (RdDM).
Richard High Ebright is an American molecular biologist. He is the Board of Governors Professor of Chemistry and Chemical Biology at Rutgers University and Laboratory Director at the Waksman Institute of Microbiology.
Tagetitoxin (TGT) is a bacterial phytotoxin produced by Pseudomonas syringae pv. tagetis.
Archaeal transcription factor B is a protein family of extrinsic transcription factors that guide the initiation of RNA transcription in organisms that fall under the domain of Archaea. It is homologous to eukaryotic TFIIB and, more distantly, to bacterial sigma factor. Like these proteins, it is involved in forming transcription preinitiation complexes. Its structure includes several conserved motifs which interact with DNA and other transcription factors, notably the single type of RNA polymerase that performs transcription in Archaea.
Lynn L. Silver is an American born scientist best known for her contributions to the field of antibacterial discovery and development. With over 30 years of experience in the antibacterial discovery field and over 70 peer reviewed publications, Silver provides insight and advice to the research community on global advisory panels, international collaborations for addressing antibiotic resistance issues. Silver has published several highly cited reviews in the field of antibacterial discovery.