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Discovery of novel antibacterials

A. Craney, F.E. Romesberg, Bioorg. Med. Chem. (2016) 24:6225-6226.
pubpic2016craneyWe serve as guest editors for a special issue of Bioorg. Med. Chem. In this preface, we give a bit of background on drug discovery and the impending crisis posed by antibiotic resistance, as well as an overview of the contributed articles.

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An alternative terminal step of the general secretory pathway in Staphylococcus aureus

A. Craney, M.M. Dix, R. Adhikary, B.F. Cravatt, F.E. Romesberg, mBio (2015) 6:e01178-15.
pubpic2015ccraneyWeidentify the S. aureus operon ayrRABC and show that once released from repression by AyrR, the protein products AyrABC together confer resistance to the SPase inhibitor arylomycin M131 by providing an alternate and novel method of releasing translocated proteins, and we demonstrate that AyrABC functionally complements SPase by mediating the processing of the normally secreted proteins. Overall, the data demonstrate that ayrRABC encodes a secretion stress-inducible alternate terminal step of the general secretory pathway.

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The inhibition of type I bacterial signal peptidase: Biological consequences and therapeutic potential

A. Craney, F.E. Romesberg, Bioorg. Med. Chem. Lett. (2015) 25:4761–4766.
pubpic2015xxWe review the information gained from the use of SPase inhibitors as probes of prokaryote biology. A thorough understanding of the consequences of SPase inhibition and the mechanisms of resistance that arise are essential to the success of SPase as an antibiotic target. In addition to the role of SPase in processing secreted proteins, the use of SPase inhibitors has elucidated a previously unknown function for SPase in regulating cleavage events of membrane proteins.

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Origins of Y. pestis sensitivity to the arylomycin antibiotics and the inhibition of type I signal peptidase

D.B. Steed, J. Liu, E. Wasbrough, L. Miller, S. Halasohoris, J. Miller, B. Somerville, J.R. Hershfield, F.E. Romesberg, Antimicrob. Agents Chemother. (2015) 59:3887-3898.
pubpic2015steedWe demonstrate that arylomycin activity is conserved against a broad range of Y. pestis strains and that this activity results from SPase inhibition. The origins of the sensitivity are traced to an increased dependence on SPase that results from high levels of protein secretion under physiological conditions.

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A putative Cro-like repressor contributes to arylomycin resistance in Staphylococcus aureus

A. Craney, F.E. Romesberg, Antimicrob. Agents Chemother. (2015) 59:3066-3074.
pubpic201craneyWe characterized the susceptibility of a panel of S. aureus strains to two arylomycin derivatives and observed a wide range of susceptibilities. We found that resistant strains were sensitized by co-treatment with tunicamycin, which inhibits the first step of wall teichoic acid synthesis. Transcriptional profiling using growth inhibitory concentrations of arylomycin revealed further insight into how this pathogen copes with secretion stress.