NIBR
POSTDOCTORAL PROGRAM

Tsuyoshi newTsuyoshi Uehara, PhD
(Co-Mentor: Charles Dean, PhD)

Infectious Diseases
Emeryville, California, United States


Options for treating Gram-negative bacterial infections are limited and current therapies are progressively less effective due to the rapid development of multi-drug resistance in the clinic. This necessitates a renewed focus on the development of novel antibacterials directed at these pathogens. However, drug discovery against Gram-negatives is a challenge because their outer membrane and active efflux conspire to prevent or reduce the access of inhibitor molecules to the intracellular space where the targets are located. This characteristic protective impermeability of the outer membrane is largely determined by lipopolysaccharide (LPS), the major component of the outer leaflet of the outer membrane. Perturbation or truncation of LPS can render the cells susceptible to several currently used drugs or investigational compounds that are usually inactive against Gram-negatives. In addition, LPS biosynthesis and its transport to the outer membrane are essential for the growth of many gram-negative bacteria. Therefore, disruption of LPS biosynthesis or assembly is a promising antibacterial pathway target and recent reports have described investigational LpxC (biosynthesis) and LptD (transport) inhibitors. Despite this interest and significant recent progress in delineating details of LPS biosynthesis/assembly, cellular and molecular mechanisms of LPS function in drug resistance and bacterial proliferation remain elusive. We employ a range of genetic, molecular biological, and microscopic techniques to better understand LPS functional roles in bacterial cells with a view to enabling novel antibacterial development or treatment strategies.

Selected Publications

Selected Publications for Tsuyoshi Uehara

An ATP-binding cassette transporter-like complex governs cell-wall hydrolysis at the bacterial cytokinetic ring.
Yang DC, Peters NT, Parzych KR, Uehara T, Markovski M, Bernhardt TG.
Proc Natl Acad Sci U S A. 2011 Nov 8;108(45):E1052-60.

Lipoprotein cofactors located in the outer membrane activate bacterial cell wall polymerases.
Paradis-Bleau C, Markovski M, Uehara T, Lupoli TJ, Walker S, Kahne DE, Bernhardt TG.
Cell. 2010 Dec 23;143(7):1110-20.

Daughter cell separation is controlled by cytokinetic ring-activated cell wall hydrolysis.
Uehara T, Parzych KR, Dinh T, Bernhardt TG.
EMBO J. 2010 Apr 21;29(8):1412-22.

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Selected Publications for Charles Dean

Identification of elongation factor G as the conserved cellular target of argyrin B.
Nyfeler B, Hoepfner D, Palestrant D, Kirby CA, Whitehead L, Yu R, Deng G, Caughlan RE, Woods AL, Jones AK, Barnes SW, Walker JR, Gaulis S, Hauy E, Brachmann SM, Krastel P, Studer C, Riedl R, Estoppey D, Aust T, Movva NR, Wang Z, Salcius M, Michaud GA, McAllister G, Murphy LO, Tallarico JA, Wilson CJ, Dean CR.
PLoS One. 2012;7(9):e42657.

Mechanisms decreasing in vitro susceptibility to the LpxC inhibitor CHIR-090 in the gram-negative pathogen Pseudomonas aeruginosa.
Caughlan RE, Jones AK, Delucia AM, Woods AL, Xie L, Ma B, Barnes SW, Walker JR, Sprague ER, Yang X, Dean CR.
Antimicrob Agents Chemother. 2012 Jan;56(1):17-27.

Lipopolysaccharide (LPS) inner-core phosphates are required for complete LPS synthesis and transport to the outer membrane in Pseudomonas aeruginosa PAO1.
Delucia AM, Six DA, Caughlan RE, Gee P, Hunt I, Lam JS, Dean CR.
MBio. 2011 Aug 2;2(4). pii: e00142-11.

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