Kevin D. Young, Ph.D.

Professor, Department of Microbiology & Immunology

Research Interest: Genetics and physiology of E. coli cell division and bacterial cell shape

Ph.D.: University of Oklahoma

Postdoctoral: Texas A&M University, University of California at Berkeley

Phone: (501) 526-6802
Fax: (501) 686-5359

Research Description

Peptidoglycan is unique to the eubacteria and is the rigid macromolecule that defines their shape, protects them from osmotic shock and lysis, and which can behave as a trans-acting signal or toxin towards eukaryotic cells. The long-term goal of my laboratory is to explain the structure, synthesis, and remodeling of bacterial peptidoglycan, with the aim of understanding its contribution to fundamental prokaryotic cell biology, bacterial pathogenesis and immunoregulation. In particular, we are addressing the following questions: What are the proteins, substrates, and products involved in the construction and maintenance of peptidoglycan? How might these processes be regulated? In what way does peptidoglycan composition and structure affect bacterial physiology? How is cell shape determined? And how does the cell determine whether to make lateral wall or a division septum?

Penicillin and its relatives, the beta-lactam antibiotics, kill bacteria by inactivating penicillin-binding proteins (PBPs), a set of enzymes responsible for the latter stages of peptidoglycan synthesis and maintenance. In Escherichia coli, the identity of seven PBPs has been known for three decades. Nevertheless, we know very little about how these proteins contribute to the physiology of a bacterial cell and cannot describe in detail the pathways by which PBPs assemble and remodel mature peptidoglycan. Although we have a wealth of biochemical data about how a few PBPs operate in isolation, this knowledge does not necessarily reflect or explain the in vivo roles of each PBP. In addition, the PBPs may have functions we do not yet know how to measure. For the most part, our in vivo knowledge of what PBPs do for the cell is based on defects that accompany mutation or inactivation of individual PBPs. However, several PBPs share common enzymatic activities so the phenotypes that accompany the loss of one protein may be masked by the action of another. Thus, in practice, the absence of most individual PBPs produces no identifiable phenotype. The end result is that we cannot answer some very basic questions about how the cell wall is built or how it contributes to the physiology of the cell envelope.

We have addressed this problem by systematically mutating PBP genes in multiple combinations to visualize new phenotypes. From a comprehensive set of over 400 multiple-deletion mutants, we found unanticipated phenotypes and previously unknown physiological roles for the PBPs and peptidoglycan. The principle effect of removing PBPs is that certain mutants cannot maintain wild type diameter or shape. The most visually dramatic discovery is of a heretofore unknown relationship between the single domain PBPs and FtsZ, the major regulator of bacterial cell division. For example, some mutants interact with a missense FtsZ protein to grow in tight spirals instead of as straight rods. In pursuing the mechanisms behind these findings, we also found that the outer membrane and proteins embedded within it are organized in a helical fashion, with implications for the synthesis of all layers of the Gram negative bacterial envelope. Finally, the practical importance of these "nonessential" PBPs appears to be much greater than supposed. Several organisms elaborate peptidoglycan-based toxins, and other wall fragments are recognized specifically by a set of peptidoglycan binding proteins (PGRPs) comprising part of the innate immune response in eukaryotes. These circumstances argue that many of the PBPs may be involved in modifying peptidoglycan to create virulence factors or to elude and manipulate host immunity. Also of practical interest are potential applications of harnessing these enzymes to construct nanometer-sized vessels of defined shapes and dimensions. In summary, understanding peptidoglycan biology has become more imperative than ever, and our mutants are a particularly valuable resource with which to approach these new problems and applications.

Reviews and Book Chapters

Kevin D. Young. 2007. Bacterial morphology: why have different shapes? Curr. Opin. Microbiol. 10:596-600.

Kevin D. Young. 2006. The selective value of bacterial shape. Microbiol. Molec. Biol. Rev. 70:660-703.

Kevin D. Young. 2006. Too many strictures on structure. Trends Microbiol. 14:155-156.

Kevin D. Young. 2003. Bacterial shape. Mol. Microbiol. 49:571-580.

David L. Popham and Kevin D. Young. 2003. Role of penicillin-binding proteins in bacterial cell morphogenesis. Curr. Opin. Microbiol. 6:594-599.

Kevin D. Young. 2001. Peptidoglycan. In :Encyclopedia of Life Sciences, John Wiley & Sons, Ltd., Chichester, http://www.els.net/ [DOI: 10.1038/npg.els.0000702].

Kevin D. Young. 2001. Approaching the physiological functions of penicillin binding proteins in Escherichia coli. Biochimie 83:99-102.

References

Archana Varma, Kerwin Huang, and Kevin D. Young. 2008. Min proteins as a general cell geometry detection system: Cell shape determines the patterns of Min protein oscillation in aberrantly shaped Escherichia coli. J. Bacteriol. 190:2106-2117.

Archana Varma, Miguel de Pedro, and Kevin D. Young. 2007. FtsZ directs a second mode of peptidoglycan synthesis in Escherichia coli. J. Bacteriol. 189:5692-5704.

Richa Priyadarshini, Miguel de Pedro, and Kevin D. Young. 2007. Role of peptidoglycan amidases in the development and morphology of the division septum in Escherichia coli. J. Bacteriol. 189:5334-5347.

Anindya S. Ghosh, Amy L. Melquist, and Kevin D. Young. 2006. Loss of O-antigen increases cell shape abnormalities in penicillin-binding protein mutants of Escherichia coli. FEMS Microbiol. Lett. 263:252-257.

Richa Priyadarshini, David L. Popham, and Kevin D. Young (2006) Daughter cell separation by penicillin binding proteins and peptidoglycan amidases in Escherichia coli. J. Bacteriol. 188:5345-5355.

Gallant, C. V., C. Daniels, J. M. Leung, A. S. Ghosh, Kevin D. Young, L. P. Kotra, and Lori L. Burrows (2005). Common Beta-lactamases inhibit bacterial biofilm formation. Mol. Microbiol. 58:1012-1024.

Anindya S. Ghosh and Kevin D. Young (2005). Helical disposition of proteins and lipopolysaccharide in the outer membrane of Escherichia coli. J. Bacteriol. 187:1913-1922.

Bernadette M. Meberg, Avery L. Paulson, Richa Priyadarshini and Kevin D. Young (2004). Endopeptidase penicillin binding proteins 4 and 7 play auxiliary roles in determining uniform morphology of Escherichia coli. J. Bacteriol. 186:8326-8336.

Archana Varma and Kevin D. Young (2004). FtsZ and low molecular weight penicillin binding proteins collaborate to create the uniform cell shape of Escherichia coli. J. Bacteriol. 186:6768-6774.

Trine Nilsen, Anindya S. Ghosh, Marcia B. Goldberg and Kevin D. Young (2004). Branching sites and morphological abnormalities behave as ectopic poles in shape-defective Escherichia coli. Molec. Microbiol. 52:1045-1054.

Shi-Yan Li, Jochem-Volker Höltje and Kevin D. Young (2004). Comparison of HPLC and fluorophore-assisted carbohydrate electrophoresis (FACE) methods for analyzing peptidoglycan composition of Escherichia coli Anal. Biochem. 326:1-12.

Francis C. Sailer, Bernadette M. Meberg, and Kevin D. Young (2003). b -Lactam induction of colanic acid gene expression in Escherichia coli. FEMS Microbiol. Lett. 226:245-249.

Anindya S. Ghosh and Kevin D. Young (2003). Sequences near the active sites of chimeric penicillin binding proteins 5 and 6 affect the ability to maintain uniform morphology of Escherichia coli. J. Bacteriol. 185:2178-2186.

Miguel A. de Pedro, Kevin D. Young, Joachim-Volker Höltje, and Heinz Schwarz (2003). Branching of Escherichia coli cells arises from multiple sites of inert peptidoglycan. J. Bacteriol. 185:1147-1152.

David E. Nelson, Anindya S. Gosh, Avery L. Paulson and Kevin D. Young (2002). Contribution of membrane-binding and enzymatic domains of penicillin binding protein 5 to maintenance of uniform cellular morphology of Escherichia coli. J. Bacteriol. 184:3630-3639.

Bernadette M. Meberg, Frances C. Sailer, David E. Nelson and Kevin D. Young (2001). Reconstruction of Escherichia coli mrcA (PBP 1a) mutants lacking multiple combinations of penicillin binding proteins. J. Bacteriol. 183:6148-6149.

David E. Nelson and Kevin D. Young (2001). Contributions of PBP 5 and DD-carboxypeptidase penicillin binding proteins to maintenance of cell shape in Escherichia coli. J. Bacteriol. 183:3055-3064.

David E. Nelson and Kevin D. Young (2000). Penicillin binding protein 5 affects cell diameter, contour and morphology of Escherichia coli. J. Bacteriol. 182:1714-1721.

Sylvia A. Denome, Pamela K. Elf, Thomas A. Henderson, David E. Nelson and Kevin D. Young (1999). Escherichia coli mutants lacking all possible combinations of eight penicillin binding proteins: viability, characteristics, and implications for peptidoglycan synthesis. J. Bacteriol. 181:3981-3993.

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