rifampicin ͉ rifapentine ͉ rifabutin ͉ RNA polymerase inhibitors ͉ antibacterial agents T he rifamycins-notably rifampicin, rifapentine, and rifabutin-are potent, broad-spectrum antibacterial agents and are the lynchpin of current antituberculosis therapy (1) [supporting information (SI) Fig. S1]. The activity of rifamycins stems from their high-affinity binding to, and inhibition of, bacterial RNA polymerase (RNAP) (2).The molecular mechanism of inhibition of RNAP by rifamycins has been investigated for four decades. Rifamycins have no or only small effects on RNAP-promoter interaction and RNAP-NTP interaction and generally have no or only small effects on formation of the RNA first phosphodiester bond (3, 4). The predominant effect of rifamycins is to block formation of the RNA second phosphodiester bond or third phosphodiester bond (when transcription is initiated with an NTP, or with an NDP or NMP, respectively) (4). RNAP that has synthesized a sufficiently long RNA product to enter into the transcriptionelongation phase is resistant to rifamycins (5). These properties led to the proposal that rifamycins inhibit RNAP through a simple steric-occlusion mechanism, in which the rifamycin binds adjacent to the RNAP active center, along the path of the RNA product, and physically prevents synthesis or retention of RNA products Ͼ2-3 nt in length (4).The crystal structure of Thermus aquaticus RNAP in complex with rifampicin showed that rifampicin binds to a site adjacent to the RNAP active center, along the path of the RNA product, in a position to physically prevent synthesis or retention of RNA products Ͼ2-3 nt in length-in complete agreement with the prediction of the steric-occlusion mechanism (6) (Figs. S2 and S3A). The structure accounts for biochemical results defining the mechanism of rifamycins and genetic results defining amino acid substitutions in RNAP that confer rifamycin resistance, and provides a basis for structure-based design of improved RNAP inhibitors (6).Recently, Artsimovitch et al. (7) proposed a new mechanism for inhibition of RNAP by rifamycins-a mechanism that is proposed to operate in addition to, or instead of, the steric- ␤-D516V, which substitute a residue located on the proposed allosteric signaling pathway, confer resistance to rifamycins but do not correspondingly reduce affinity of RNAP for rifamycins. (iii) The designed rifamycin-resistant mutant ␤-L1235A, which substitutes a residue located on the proposed allosteric signaling pathway, confers resistance to rifamycins but does not correspondingly reduce affinity of RNAP for rifamycins.In this work, we directly tested the principal premise of the model of Artsimovitch et al. (7): i.e., the premise that rifamycins decrease the affinity of binding of Mg 2ϩ to the RNAP active center. We find that rifamycins do not affect the affinity of binding of Mg 2ϩ to the RNAP active center. In addition, weAuthor contributions: A.F

The sluggish kinetics of ethanol oxidation reaction (EOR), poor C1 selectivity and susceptibility to toxicity of CO intermediates hinder the commercialization of direct ethanol fuel cells (DEFCs). In this paper,...

For new composite materials with functional nanoparticles (NPs) embedded in metal organic frameworks (MOFs), rational design and precise control over their architectures are imperative for achieving enhanced performance and novel functions. Especially in catalysis, the activity and selectivity of such composite materials are strongly determined by the encapsulation state and thickness of the MOF shell, which greatly influences the diffusion and adsorption of substance molecules onto the NP surface. In this study, MOF-74(Ni)-encapsulated Rh-Ni hierarchical heterostructures (Rh-Ni@MOF-74(Ni)) were successfully constructed using magnetic Rh-Ni-alloyed nanoflowers (NFs) as a self-sacrificial template. Strikingly, the encapsulation state and thickness of the formed MOF shell were well-tuned via template dealloying by changing the Ni content in the Rh-Ni NFs template. More interestingly, such unique Rh-Ni composites encapsulated with MOFs as catalysts could be magnetically recyclable and exhibited enhanced catalytic performance for the selective hydrogenation of alkynes to cis products, owing to the confinement effect of the MOF shell, as compared to their pristine counterparts.