CbtA toxin of Escherichia coli inhibits cell division and cell elongation via direct and independent interactions with FtsZ and MreB.

The toxin components of toxin-antitoxin modules, found in bacterial plasmids, phages, and chromosomes, typically target a single macromolecule to interfere with an essential cellular process. An apparent exception is the chromosomally encoded toxin component of the E. coli CbtA/CbeA toxin-antitoxin module, which can inhibit both cell division and cell elongation. A small protein of only 124 amino acids, CbtA, was previously proposed to interact with both FtsZ, a tubulin homolog that is essential for cell division, and MreB, an actin homolog that is essential for cell elongation. However, whether or not the toxic effects of CbtA are due to direct interactions with these predicted targets is not known. Here, we genetically separate the effects of CbtA on cell elongation and cell division, showing that CbtA interacts directly and independently with FtsZ and MreB. Using complementary genetic approaches, we identify the functionally relevant target surfaces on FtsZ and MreB, revealing that in both cases, CbtA binds to surfaces involved in essential cytoskeletal filament architecture. We show further that each interaction contributes independently to CbtA-mediated toxicity and that disruption of both interactions is required to alleviate the observed toxicity. Although several other protein modulators are known to target FtsZ, the CbtA-interacting surface we identify represents a novel inhibitory target. Our findings establish CbtA as a dual function toxin that inhibits both cell division and cell elongation via direct and independent interactions with FtsZ and MreB.

UK-1 and structural analogs are potent inhibitors of hepatitis C virus replication.

The bacterial natural product UK-1 and several structural analogs inhibit replication of the hepatitis C virus in the replicon assay, with IC50 values as low as 0.50 µM. The NS3 helicase has been identified as a possible target of inhibition for several of these compounds, while the remaining inhibitors act via an undetermined mechanism. Gel shift assays suggest that helicase inhibition is a direct result of inhibitor-enzyme binding as opposed to direct RNA binding, and the ATPase activity of NS3 is not affected. The syntheses and biological results are presented herein.

Switching to less expensive blindness drug could save medicare part B $18 billion over a ten-year period.

The biologic drugs bevacizumab and ranibizumab have revolutionized treatment of diabetic macular edema and neovascular age-related macular degeneration, leading causes of blindness. Ophthalmologic use of these drugs has increased and now accounts for roughly one-sixth of the Medicare Part B drug budget. The two drugs have similar efficacy and potentially minor differences in adverse-event rates; however, at $2,023 per dose, ranibizumab costs forty times more than bevacizumab. Using modeling methods, we predict ten-year (2010-20) population-level costs and health benefits of using bevacizumab and ranibizumab. Our results show that if all patients were treated with the less expensive bevacizumab instead of current usage patterns, savings would amount to $18 billion for Medicare Part B and nearly $5 billion for patients. With an additional $6 billion savings in other health care expenses, the total savings would be almost $29 billion. Altering patterns of use with these therapies by encouraging bevacizumab use and hastening approval of biosimilar therapies would dramatically reduce spending without substantially affecting patient outcomes.