Professor of Biology
Director of the Biotechnology Program
Ph.D., Johns Hopkins University, 1979
Helen Hay Whitney Postdoctoral Fellow, Stanford University, 1979-1982

Program Affiliation: Molecular Biology & Genetics | Microbiology

Research Groups Affiliation: Biochemistry | Genetics | Genomics & Bioinformatics | Microbiology

Phone: 812/856-1318
Fax: 812/855-6705
Email Malcolm

Winkler Lab website

Background and Past Research Interests. I received my Ph.D. degree in Biology at the Johns Hopkins University in Philip Hartman's laboratory where I worked on regulation of the histidine operon and on cleavage of the 23S rRNA of Salmonella typhimurium LT2. Next, I was a Helen Hay Whitney Postdoctoral Fellow in the Department of Biology at Stanford University in Charles Yanofsky's laboratory where I worked on the mechanism of pausing in attenuation control of the tryptophan operon of Escherichia coli K-12. Following this postdoctoral training in 1982, I became an Assistant and then an Associate Professor in the Department of Molecular Biology at Northwestern University Medical School in Chicago. I moved my laboratory to the Department of Microbiology and Molecular Genetics at the University of Texas Houston Medical School in 1990, where I became a Full Professor. In 1999, I became a Research Advisor (Director equivalent on the research track) in the Division of Infectious Diseases Research at Lilly Research Laboratory, which is a division of Eli Lilly and Company. I joined the faculty at Indiana University Bloomington as a Professor of Biology in May, 2003. I currently serve on the Editorial Boards of the Journal of Bacteriology, Antimicrobial Agents and Chemotherapy, and Annual Reviews of Microbiology. I am currently a member of the NSF Proposal Review Panel in Prokaryotic Cell and Molecular Biology. In the past, I have served on the NIH Microbial Genetics and Physiology Study Section and been an ad hoc reviewer for other granting agencies and journals.

My research interests before moving to Lilly Research Laboratories centered on three areas of bacterial genetics and physiology in an Escherichia coli K-12 model system: 1) Regulation of pyridoxal 5'-phosphate coenzyme biosynthesis, which serves as an important model of pathway evolution and metabolic integration. 2) Regulation of the mutS, mutL , and mutH mismatch repair genes, which play fundamental roles in mutagenesis, preventing homeologous recombination, and the evolution of antibiotic resistance. 3) The structure and regulation of the miaA - hfq superoperon and the enzymology and function of the MiaA tRNA modification enzyme and the Hfq global RNA chaperone. At Lilly Research Laboratories, I led several projects to discover new antibiotics to battle bacterial resistance and chronic diseases linked to bacterial infections. I was also involved in the development of novel technologies to accelerate antibacterial and antiviral drug discovery. My laboratory at Lilly continued to perform basic research to understand the roles and integration of two-component regulatory systems (TCSs), proteases such as ClpP, key biosynthetic pathways, such as those for purine and pyridoxal 5'-phosphate biosynthesis, and translational regulatory mechanisms in the physiology, antibiotic sensitivity, and pathogenesis of human bacterial pathogens, using Streptococcus pneumoniae and Haemophilis influenzae as model gram-positive and gram-negative organisms, respectively.

Current Research Interests. My laboratory at Indiana University Bloomington is continuing the following four lines of basic investigations in Streptococcus pneumoniae physiology, pathogenesis, and genomics. We have the following four research interests: (1) Functions and signal transduction of the essential VicRK (YycFG) and other non-essential two-component regulatory systems in Streptococcus pneumoniae. (2) Function and interactions of the essential PcsB putative cell wall hydrolase and related surface proteins that are important for cell wall biosynthesis and virulence of Streptococcus pneumoniae. (3) Mechanisms of translation control in Streptococcus pneumoniae, including gene expression patterns induced by sublethal concentrations of antibiotics and regulatory mutations.(4) Genomic organization of pathogenic serotype 2 strains of Streptococcus pneumoniae, including determination of the genomic sequence of the genetically and historically important strain D39. My laboratory uses a wide range of approaches to address key questions in these research areas, including genetics, molecular biology, preparative and analytical biochemistry, physiological characterization and microscopy, genomics, proteomics, and microarray analysis.

Winkler, M. E. and J. A. Hoch. 2008. Essentiality, Bypass, and Targeting of the YycFG (VicRK) Two-Component Regulatory System in Gram-Positive Bacteria. J. Bacteriol. published 1 February 2008, 10.1128/JB.01682-07 http://jb.asm.org/cgi/content/abstract/JB.01682-07v1?papetoc.

Ramos-Montañez S., H.-C. T. Tsui, K. J. Wayne, J. L. Morris, L. E. Peters, F. Zhang, K. M. Kazmierczak, L.-T. Sham, and M. E. Winkler. 2008. Polymorphism and Regulation of the spxB (Pyruvate Oxidase) Virulence Factor Gene by a CBS-HotDog Domain Protein (SpxR) in Serotype 2 Streptococcus pneumoniae. Mol. Microbiol. 67: 729-746.

Lanie J.A., W.-L. Ng, K. M. Kazmierczak, T. M. Andrzejewski, T. M. Davidsen, K. J. Wayne, H. Tettelin, J. I. Glass, and M. E. Winkler. 2006. Genome Sequence of Avery's Virulent Serotype 2 Strain D39 of Streptococcus pneumoniae and Comparison With That of Unencapsulated Laboratory Strain R6. J. Bacteriol. 189: 38-51.

Ng, W.-L, H-C. T. Tsui, and M. E. Winkler. 2005. Regulation of the pspA Virulence Factor and Essential pcsB Murein Biosynthetic Genes by Phosphorylated VicR (YycF) Response Regulator in Streptococcus pneumoniae. J. Bacteriol. 187 : 7444-7459.

Gilmour R., J. E. Foster, Q. Sheng, J. R. McClain, A. Rilly, P.-M. Sun, W.-L. Ng, D. Yan, T. I. Nicas, K. Henry, and M. E. Winkler. 2005. A New Class of Competitive Inhibitor of Bacterial Histidine Kinases. J. Bacteriol. 187 : 8196-8200.

Ng, W.L., K.M. Kazmierczak, and M.E. Winkler. 2004. Defective Cell Wall Synthesis in Streptococcus pneumoniae R6 Depleted for the Essential PcsB Putative Murein Hydrolase or the VicR (YycF) Response Regulator. Mol. Microbiol. 53: 1161-1175 (including cover picture for this issue).

Ng, W. L. and M.E. Winkler. 2004. Singular Structures and Operon Organizations of Essential Two Component Systems in Species of Streptococcus. Microbiology, 150: 3096-3098.

Gooding, K.B., R. Higgs, B. Hodge, E. Staffer, B. Heinz, K. McKnight, K. Phipps, M. Shapiro, M. Winkler, W.-L. Ng, and R.K. Julian. 2004. High throughput screening of library compounds against an oligonucleotide substructure of an RNA target. J Am Soc Mass Spectrom 15: 884-892.

Foster, J.E., Q. Sheng, J.R. McClain, M. Bures, T.I. Nicas, K. Henry, M.E. Winkler, and R. Gilmour. 2004. Kinetic and Mechanistic Analyses of New Classes of Inhibitors of Two-Component Signal Transduction Systems Using a Coupled Assay Containing HpkA-DrrA from Thermotoga maritima. Microbiology 150: 885-896.

Ng, W.L., G.T. Robertson, K.M. Kazmierczak, J. Zhao, R. Gilmour, and M.E. Winkler. 2003. Constitutive Expression of PcsB Suppresses the Requirement for the Essential VicR (YycF) Response Regulator in Streptococcus pneumoniae R6. Mol. Microbiol. 50: 1647-1663.