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Matano, Leigh

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Matano

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Leigh

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Matano, Leigh
Author's Publications: search.filters.isAuthorOfPublication.2ddda2f1-a7b2-456b-85be-2c01a59798ec

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    A synthetic lethal approach for compound and target identification in Staphylococcus aureus
    (2015) Pasquina, Lincoln; Maria, John P. Santa; Wood, B. McKay; Moussa, Samir H.; Matano, Leigh; Santiago, Marina; Martin, Sara; Lee, Wonsik; Meredith, Timothy; Walker, Suzanne
    The majority of bacterial proteins are dispensable for growth in the laboratory, but nevertheless play important physiological roles. There are no systematic approaches to identify cell-permeable small molecule inhibitors of these proteins. We demonstrate a strategy to identify such inhibitors that exploits synthetic lethal relationships both for small molecule discovery and for target identification. Applying this strategy in Staphylococcus aureus, we have identified a compound that inhibits DltB, a component of the teichoic acid D-alanylation machinery, which has been implicated in virulence. This D-alanylation inhibitor sensitizes S. aureus to aminoglycosides and cationic peptides and is lethal in combination with a wall teichoic acid inhibitor. We conclude that DltB is a druggable target in the D-alanylation pathway. More broadly, the work described demonstrates a systematic method to identify biologically active inhibitors of important bacterial processes that can be adapted to numerous organisms.
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    A new platform for ultra-high density Staphylococcus aureus transposon libraries
    (BioMed Central, 2015) Santiago, Marina; Matano, Leigh; Moussa, S; Gilmore, Michael; Walker, Suzanne; Meredith, Timothy
    Background: Staphylococcus aureus readily develops resistance to antibiotics and achieving effective therapies to overcome resistance requires in-depth understanding of S. aureus biology. High throughput, parallel-sequencing methods for analyzing transposon mutant libraries have the potential to revolutionize studies of S. aureus, but the genetic tools to take advantage of the power of next generation sequencing have not been fully developed. Results: Here we report a phage-based transposition system to make ultra-high density transposon libraries for genome-wide analysis of mutant fitness in any Φ11-transducible S. aureus strain. The high efficiency of the delivery system has made it possible to multiplex transposon cassettes containing different regulatory elements in order to make libraries in which genes are over- or under-expressed as well as deleted. By incorporating transposon-specific barcodes into the cassettes, we can evaluate how null mutations and changes in gene expression levels affect fitness in a single sequencing data set. Demonstrating the power of the system, we have prepared a library containing more than 690,000 unique insertions. Because one unique feature of the phage-based approach is that temperature-sensitive mutants are retained, we have carried out a genome-wide study of S. aureus genes involved in withstanding temperature stress. We find that many genes previously identified as essential are temperature sensitive and also identify a number of genes that, when disrupted, confer a growth advantage at elevated temperatures. Conclusions: The platform described here reliably provides mutant collections of unparalleled genotypic diversity and will enable a wide range of functional genomic studies in S. aureus. Electronic supplementary material The online version of this article (doi:10.1186/s12864-015-1361-3) contains supplementary material, which is available to authorized users.