Faculty & Research
Indiana Molecular Biology Institute
- Contact Information
- Contact Malcolm Winkler by winklerm [at] indiana [dot] edu
- By telephone: 856-1318/6-1184/6-1781
- JH A414 / JH A410 (lab)
- Research Areas
- Genomics and Bioinformatics
- Microbial Cell Biology and Environmental Responses
- Microbial Interactions and Pathogenesis
Ph.D., Johns Hopkins University
Helen Hay Whitney Postdoctoral Fellow, Stanford University
Infectious Diseases Research Advisor, Eli Lilly and Company, 1999-2003
Young Investigator Award, American Society of Microbiology
Dissertation Opponent and Lecturer, Umeå University, Sweden
Dissertation Opponent and Lecturer, University of Groningen, Netherlands
Fellow, American Academy of Microbiology (AAM)
Fellow, American Association for the Advancement of Science (AAAS)
Streptococcus pneumoniae (pneumococcus) is an extremely serious human opportunistic respiratory pathogen that kills well over two million people annually worldwide. Multidrug resistance is increasing in S. pneumoniae clinical isolates at an alarming rate, and drug-resistant S. pneumoniae is considered as a serious threat to health in the USA by the CDC.
The general goal of my research program is to understand signal transduction, regulatory mechanisms, and supramolecular complexes that mediate the stress responses, metabolism, cell structure, and pathogenesis of this bacterium. At one level, our work is providing fundamental information about the roles played by physiology, protein complexes, and metabolism in the pathogenesis of this bacterial species. At another level, we are gaining insights into the biology of S. pneumoniae, and by inference other Streptococcus species, which are distinctive, fascinating organisms that carry out many processes by mechanisms different from those of model bacteria like Bacillus subtilis. Therefore, besides understanding pathogenesis, there is the expectation of learning new biological principles from studies of S. pneumoniae.
Most of our current work focuses on the mechanisms of peptidoglycan cell wall biosynthesis in S. pneumoniae mediated by gene control and protein interactions. In particular, we are working to solve the “3 C Problem” of composition, chronology, and coordination of the protein molecular machines that synthesize and remodel peptidoglycan during cell division of bacteria in culture and in contact with host cells.
These investigations have very real practical implications in the discovery of new targets for antibiotic and vaccine development. In pursuit of these goals, we use a combination of sophisticated physiology, molecular genetics, biochemistry, and cell biology along with tissue-culture and other models of colonization and infection.
Rued, B. E. J. J. Zheng, A. Mura, H.-C. T. Tsui, M. J. Boersma,. J. L. Mazny, F. Corona, A. J. Perez, D. Fadda, L. Doubravová, L. Buriankiva, P. Branny, O. Massidda, and M. E. Winkler. (2017). Suppression and Synthetic-Lethal Genetic Relationships of ΔgpsB Mutations Indicate that GpsB Mediates Protein Phosphorylation and Penicillin-Binding Protein Interactions in Streptococcus pneumoniae D39. Molec Microbiol, in press. doi: 10.1111/ mmi.13613. (PMID 28010038; PMC in progress).
Subject of MicroCommentary: R. J. Lewis. (2017) The GpsB Files: The Truth is Out There. Molec Microbiol doi: 10.1111/mmi.13612.
- Mura A, D. Fadda, A. J. Perez, M. L. Danforth, D. Musu, A. I. Rico, M. Krupka, D. Denapaite D, H. T. Tsui, M. E. Winkler, P. Branny P, M. Vicente, W. Margolin, O. Massidda. Roles of Essential FtsA in Cell Growth and Division of Streptococcus pneumoniae. (2017) J. Bacteriol, in press. doi: 10.1128/JB.00608-16. (PMID 27872183 (PMC in progress).
- Lisher, J. P., H.-C. T. Tsui, S. Ramos-Montnaez, K. L. Hentchel, K. S. Carroll, M. E. Winkler, and D. P. Giedroc. (2017). Chemical and Biological Adaptation to Endogenous Hydrogen Peroxide Production in Streptococcus pneumoniae D39. mSphere 2(1): e00291-16. (PMC in progress).
- Tsui, H.-C. T., J. J. Zheng, A. N. Magallon, J. D. Ryan, R. Yunck, B. E. Rued, T. G. Bernhardt, and M. E. Winkler. (2016). Suppression of a Deletion Mutation in the Gene Encoding Essential PBP2b Reveals a New Lytic Transglycosylase Involved in Peripheral Peptidoglycan Synthesis in Streptococcus pneumoniae D39. Molec Microbiol 100:1039-65. doi: 10.1111/mmi.13366 (PMID26933838; PMC in progress).
Cover photo of Volume 100, Number 6 (June) of Molecular Microbiology.
- Fu, Y., K. E. Bruce, B. E. Rued, M. E. Winkler, and D. P. Giedroc. (2016). 1H, 13C, 15N Resonance Assignments of the Extracellular Loop 1 Domain (ECL1) of Streptococcus pneumoniae D39 FtsX, an Essential Cell Division Protein. Biomolec NMR Assign, 10: 89-92. doi: 10.1007/s12104-015-9644-9 (PMC4789122).
- Bajaj, R., K. E. Bruce, A. L. Davidson, B. E. Rued, C. V. Stauffacher, and M. E. Winkler. (2016). Biochemical Characterization of Essential Cell Division Proteins FtsX and FtsE That Mediate Peptidoglycan Hydrolysis by PcsB in Streptococcus pneumoniae. MicrobiologyOpen. doi: 10.1002/mbo3.366 (PMID: 27167971; PMC in progress).
- Zheng, J. J., D. Sinha, K. J. Wayne, and M.E. Winkler. (2016). Physiological Roles of the Dual Phosphate Transporter Systems in Low and High Phosphate Conditions and in Capsule Maintenance of Streptococcus pneumoniae D39. Front Cell Infect Microbiol 6:63. doi: 10.3389/fcimb.2016.00063. eCollection 2016 (PMC4913102).
Boersma, M. J., E. Kuru, J. T. Rittichier, M. S. VanNieuwenhze, Y,V. Brun, and M. E. Winkler. (2015). Minimal Peptidoglycan Turnover in Wild-Type and PG Hydrolase and Cell Division Mutants of Streptococcus pneumoniae D39 Growing Planktonically and In Host-Relevant Biofilms. J Bacteriol. 197: 3472-3485 (PMC4621067).
Kocaoglu O, Tsui HC, Winkler ME, Carlson EE. (2015). Profiling of β-Lactam Selectivity for Penicillin-Binding Proteins in Streptcoccus pneumoniae D39. Antimicrob Agents Chemother. 59:3548-3555.
Hoover SE, Perez AJ, Tsui HC, Sinha D, Smiley DL, DiMarchi RD, Winkler ME, Lazazzera BA.(2015). A new quorum sensing system (TprA/PhrA) for Streptococcus pneumoniae D39 that regulates a lantibiotic biosynthesis gene cluster. Molecular Microbiology, in press, published on-line Apr 13. doi: 10.1111/mmi.13029. [Epub ahead of print]. PMID: 25869931 (PMC in process).
Subject of MicroCommentary: Monnet V, Gardan R. (2015). Quorum-sensing regulators in Gram-positive bacteria: “cherchez le peptide.” Molecular Microbiology, in press, published on-line May 19. doi: 10.1111/mmi 13060 [Epub ahead of print]. PMID: 25988215.
Tsui H.-C. T., M. J. Boersma, S. A. Vella, O. Kocaoglu, E. Kuru E, J. K. Peceny, E. E. Carlson, M. S. VanNieuwenhze, Y. V. Brun, S. L. Shaw, and M. E. Winkler. (2014). Pbp2x Localizes Separately from Pbp2b and Other Peptidoglycan Synthesis Proteins During Laters Stages of Cell Division of Streptococcus pneumoniae D39. Molec Microbiol 94:21-40. (PMC4209751).
Cover photo of volume 94, number 1 (October) of Molecular Microbiology. MicroCommentary: Cadby I.T. and A. L. Lovering. 2014. Molecular Surveillance of the Subtle Septum: Discovering a New Mode of Peptidoglycan Synthesis in Streptococcus. Molec Microbiol 94: 1-4.
Yue F, H.-C. T. Tsui, K. E. Bruce, L.-T. Sham, K. A. Higgins, J. P. Lisher, K. M. Kazmierczak, M. J. Maroney, C. E. Dann III, M. E. Winkler, and D. P. Giedroc. (2013). A New Structural Paradigm in Copper Resistance in Streptococcus pneumoniae. Nature Chem Biol 9: 177-83. (PMC3578076).
Land, A.D., H.-C. T. Tsui, O. Kocaoglu, S. Vella, S. L. Shaw, S. K. Keen, L.-T. Sham, E. E. Carlson, and M. E. Winkler. (2013). Requirement of Essential Pbp2x and GpsB for Septal Ring Closure in Streptococcus pneumoniae D39. Molec Microbiol 90: 939-55.(PMC4120849).
Cover photo of volume 90, number 5 (December) of Molecular Microbiology.
Sham, L. T., K. R. Jensen, K. E. Bruce, and M. E. Winkler. (2013). Involvement of FtsE ATPase and FtsX Extracellular Loops 1 and 2 in FtsEX:PcsB Complex Function in Cell Division of Streptococcus pneumoniae D39. MBio 4: pii: e00431-13. doi: 10.1128/mBio.00431-13. (PMC3735124).
Wayne, K. J., S. Li, K. M. Kazmierczak, H.-C. T. Tsui, and M. E. Winkler. (2012). Involvement of WalK (VicK) Phosphatase Activity in Setting WalR (VicR) Response Regulator Phosphorylation Level and Limiting Crosstalk in Streptococcus pneumoniae D39 Cells. Molec Microbiol 86:645-60. (PMC3638944).
Sham, L.-T,, H.-C. T. Tsui, A. D. Land, S. M. Barendt, and M. E. Winkler. (2012). Recent Advances in Pneumococcal Peptidoglycan Biosynthesis Suggest New Vaccine and Antimicrobial Targets. Curr Opin Microbiol. 15:194-203. (PMC3322672).
Kocaoglu, O., R. A. Calvo, L.T. Sham, L. M. Cozy, S. Francis, B. R. Lanning, M. E. Winkler, D. B. Kearns, and E. E. Carlson. (2012). Selective Penicillin-Binding Protein Imaging Probes Reveal Substructure in Bacterial Cell Division. ACS Chem Biol 7: 1746-1753. (PMC3663142). Highlighted by the Faculty of 1000.
- Hsueh, Y.-H., L. M. Cozy, L.-T. Sham, R. A. Calvo, A. D. Gutu, M. E. Winkler, and D. B. Kearns. (2011). DegU-Phosphate Activates Expression of the Anti-Sigma Factor FlgM in Bacillus subtilis. Molec. Microbiol. 81: 1092-1108.
- Sham, L.-T., S. M. Barendt, K. E. Kopecky, and M. E. Winkler. (2011). Essential PcsB Putative Peptidoglycan Hydrolase Interacts with the Essential FtsXSpn Cell Division Protein in Streptococcus pneumoniae D39. Proc. National Acad. of Sci., U. S. A. 108: 1061-2069.
- Land, A. D., and M. E. Winkler (2011). Requirement for Pneumococcal MreC and MreD Is Relieved by Inactivation of the Gene Encoding PBP1a. J. Bacteriol. 193: 4166-4179.
- Major textbook: Wilson, B. A., A. A. Salyers, D. D. Whitt, and M. E. Winkler. (2011). Bacterial Pathogenesis - A Molecular Approach. Third Edition. ASM Press. Washington, D. C.
- Biller, S. J., K. J. Wayne, M. E. Winkler, and W. F. Burkholder. (2011). The Putative Hydrolase YycJ (WalJ) Affects the Coordination of Cell Division with DNA Replication in Bacillus subtilis and May Play a Conserved Role in Cell Wall Metabolism. J. Bacteriol. 193:896-908.
- Jacobsen, F. E., K. M. Kazmierczak, J. P. Lisher, M. E. Winkler, and D. P. Giedroc. (2011). Interplay between Manganese and Zinc Homeostasis in the Human Pathogen Streptococcus pneumoniae. Metallomics 3: 38-41. [cover article].
- Barendt, S. M., L.-T. Sham, and M. E. Winkler. (2011). Characterization of Mutants Deficient in the L,D-Carboxypeptidase (DacB) and WalRK-Spn (VicRK) Regulon Involved in Peptidoglycan Maturation of Streptococcus pneumoniae Serotype 2 Strain D39. J. Bacteriol. 193: 2290-2300.
- Tsui, H.-C. T., S. K. Keen, L.-T. Sham, K. J. Wayne, and M. E. Winkler. (2011). Dynamic Distribution of the SecA and SecY Translocase Subunits and Septal Localization of the HtrA Surface Chaperon/Protease During Cell Division of Streptococcus pneumoniae D39. mBio 2(5). pii: e00202-11. doi: 10.1128/mBio.00202-11.
- Nichols, R. J., Y. J. Choo, S. Sen, P. Beltrao, M. Zietek, R. Chaba, S. Lee, K. M. Kazmierczak, K. J. Lee, A. Wong, M. Shales, S. Lovett, M. E. Winkler, N. J. Krogan, A. Typas, and C. A. Gross. (2011). Phenotypic Landscape of a Bacterial Cell. Cell 144:1-14.
- Wayne, K. J., L.-T. Sham, H.-C. T. Tsui, A. D. Gutu, S. M. Barendt, S. K. Keen, and M. E. Winkler. (2010). Localization and Cellular Amounts of the WalRKJSpn (VicRKX) Two-Component Regulatory System Proteins in Serotype 2 Streptococcus pneumoniae. J. Bacteriol. 192: 4388-4394. .
- Tsui, H.-C. T., D. Mukherjee, V. A. Ray, L.-T. Sham, A. L. Feig, and M. E. Winkler. (2010). Identification and Characterization of Non-Coding Small RNAs in Streptococcus pneumoniae Serotype 2 Strain D39. J. Bacteriol 192:264-279.
- Reyes-Caballero, H, A. J. Guerra, F. E. Jacobsen, K. M. Kazmierczak, D. Cowart, U. M. Kumar-Koppolu, R. A. Scott, M. E. Winkler, and D. P. Giedroc. (2010). The Metalloregulatory Zinc Site in Streptococcus pneumoniae AdcR, A Zinc-Activated MarR Family Repressor. J. Mol. Biol. 403:197-216.
- Gutu, A. D., K. J. Wayne, L-T. Sham, and M. E. Winkler. (2010). Kinetic Characterization of the WalRKSpn (VicRK) Two-Component System of Streptococcus pneumoniae: Dependence of WalKSpn (VicK) Phosphatase Activity on Its PAS Domain. J. Bacteriol. 192: 2346-2358..
- Ramos-Montañez, S., K. M. Kazmierczak, K. L. Hentchel, and M. E. Winkler. (2010). Instability of ackA (Acetate Kinase) Mutations and Their Effects on Acetyl Phosphate (AcP) and ATP Amounts in Streptococcus pneumoniae D39. J. Bacteriol. 192: 6390-6400.
- Barendt, S. M., A. D. Land, L.-T. Sham, W.-L. Ng, H.-C. T. Tsui, R. J. Arnold, and M. E. Winkler. (2009). Capsule Influences the Cell Shape and Chain Length of pcsB Mutants in Serotype 2 Streptococcus pneumoniae. J. Bacteriol 191: 3024-3040. [cover article].
- Kazmierczak, K. M., K. J. Wayne, A. Rechtsteiner, and M. E. Winkler. (2009). Roles of relSpn in the Stringent Response, Global Regulation, and Virulence of Serotype 2 Streptococcus pneumoniae. Molec Micro 72: 590-611.