Basis of narrow-spectrum activity of fidaxomicin on Clostridioides difficile.

Fidaxomicin (Fdx) is widely used to treat Clostridioides difficile (Cdiff) infections, but the molecular basis of its narrow-spectrum activity in the human gut microbiome remains unknown. Cdiff infections are a leading cause of nosocomial deaths. Fidaxomicin, which inhibits RNA polymerase, targets Cdiff with minimal effects on gut commensals, reducing recurrence of Cdiff infection.

The antibiotic sorangicin A inhibits promoter DNA unwinding in a rifampicin-resistant RNA polymerase.

Rifampicin (Rif) is a first-line therapeutic used to treat the infectious disease tuberculosis (TB), which is caused by the pathogen (). The emergence of Rif-resistant (Rif) presents a need for new antibiotics. Rif targets the enzyme RNA polymerase (RNAP).

Diverse and unified mechanisms of transcription initiation in bacteria.

Transcription of DNA is a fundamental process in all cellular organisms. The enzyme responsible for transcription, RNA polymerase, is conserved in general architecture and catalytic function across the three domains of life. Diverse mechanisms are used among and within the different branches to regulate transcription initiation.

Transcription initiation in mycobacteria: a biophysical perspective.

Recent biophysical studies of mycobacterial transcription have shed new light on this fundamental process in a group of bacteria that includes deadly pathogens such as ( ( (), as well as the nonpathogenic (). Most of the research has focused on , the causative agent of tuberculosis (TB), which remains one of the top ten causes of death globally. The enzyme RNA polymerase (RNAP) is responsible for all bacterial transcription and is a target for one of the crucial antibiotics used for TB treatment, rifampicin (Rif).

Structures of an RNA polymerase promoter melting intermediate elucidate DNA unwinding.

A key regulated step of transcription is promoter melting by RNA polymerase (RNAP) to form the open promoter complex. To generate the open complex, the conserved catalytic core of the RNAP combines with initiation factors to locate promoter DNA, unwind 12-14 base pairs of the DNA duplex and load the template-strand DNA into the RNAP active site. Formation of the open complex is a multi-step process during which transient intermediates of unknown structure are formed.

Fidaxomicin jams RNA polymerase motions needed for initiation via RbpA contacts.

Fidaxomicin (Fdx) is an antimicrobial RNA polymerase (RNAP) inhibitor highly effective against RNAP in vitro, but clinical use of Fdx is limited to treating intestinal infections due to poor absorption. To identify the structural determinants of Fdx binding to RNAP, we determined the 3.4 Å cryo-electron microscopy structure of a complete RNAP holoenzyme in complex with Fdx.

Structure, Regulation, and Inhibition of the Quorum-Sensing Signal Integrator LuxO.

In a process called quorum sensing, bacteria communicate with chemical signal molecules called autoinducers to control collective behaviors. In pathogenic vibrios, including Vibrio cholerae, the accumulation of autoinducers triggers repression of genes responsible for virulence factor production and biofilm formation. The vibrio autoinducer molecules bind to transmembrane receptors of the two-component histidine sensor kinase family.

Selective manipulation of ICT and PET Processes in styryl-Bodipy derivatives: applications in molecular logic and fluorescence sensing of metal ions.

Remarkably versatile chemistry of Bodipy dyes allows the design and straightforward synthesis of multivalent-multitopic derivatives, which, with judicious selection of metal ion-ligand pairs based on known affinities, affords control and manipulation of photoinduced electron transfer and internal charge transfer processes as desired. We have demonstrated that metal ions acting as modulators (or inputs, in digital design parlance) can generate absorbance changes in accordance with the operation of a half-adder. In addition, an AND logic gate in the emission mode was delivered using a different binucleating arrangement of ligands.

Engineering a uranyl-specific binding protein from NikR.

A new pick-up line: The first uranyl-selective DNA-binding protein is designed using the E. coli nickel(II)-responsive protein NikR as the template. The resulting NikR' protein binds uranyl (see picture) with a dissociation constant K(d) = 53 nM and selectively binds to DNA in the presence of uranyl.