William G. Gutheil, Ph.D.

Professor

UMKC School of Pharmacy
2464 Charlotte St.
HSB 5258
Kansas City, MO 64108

 

Phone: 816-235-2424
Email: gutheilw@umkc.edu

bio-t-Bill-Gutheil (1)

Biography:

EDUCATION

California Polytechnic State University,
San Louis Obispo, CA
B.S.
1983
Biochemistry

University of Southern California,
Los Angeles, CA
Ph.D.
1989
Chemistry (Bio-Organic)

Harvard Medical School,
Boston, MA
Postdoc
1989-91
Enzymology/Molecular Biology

Tufts University,
Boston, MA
Postdoc
1991-94
Enzymology/Bio-Organic Chemistry

RESEARCH INTERESTS

Bacterial cell wall biosynthesis and related antibacterial agents. Our primary research focus is in the area of antibacterial agents targeting bacterial cell wall biosynthesis, the enzyme targets of these agents, the identification and development of new agents targeting this pathway, and the characterization of resistance to such agents. One of our key strengths is in the area of analytical biochemistry, and we have developed widely used and innovative assays for the penicillin-binding proteins (PBPs), including PBP2a from MRSA and other high-molecular mass PBPs – which are particularly challenging enzymes. We have also developed stereospecific, sensitive and precise LC-MS/MS methods for bacterial cell wall metabolites, such as L-Ala, D-Ala, and D-Ala-D-Ala, which enables the in vivo characterization of agents targeting this metabolic pathway, and resistance mechanisms (e.g. vancomycin resistance) which circumvent this pathway. This effort has been extended to the UDP-linked intermediates in the bacterial cell wall biosynthesis pathway, which provides an unprecedented ability to rapidly profile the effect of cell wall biosynthesis inhibitors on the key metabolites in this pathway. We have also identified D-boroAla as an antibacterial agent that targets D-Ala-D-Ala ligase in the bacterial cell wall biosynthesis pathway.

Biological applications of LC-MS/MS technology. Dr. Gutheil established and oversees the Drug Discovery and Metabolomics LC-MS/MS shared instrumentation resource in the School of Pharmacy. This facility currently houses two AB Sciex QTrap LC-MS/MS instruments, and a Biomek 3000 liquid handling workstation. Faculty and graduate students in the School of Pharmacy and other UMKC units are provided training and hands on access to these instruments for use in small to medium sized molecule research. This facility is heavily used and very productive. Efforts to enhance this resource are ongoing.

REPRESENTATIVE PEER-REVIEWED PUBLICATIONS

Gutheil, W. G. A sensitive equilibrium-based assay for D-lactate using D-lactate dehydrogenase: application to penicillin-binding protein/DD-carboxypeptidase activity assays. Anal Biochem 1998, 259, 62-67. http://www.ncbi.nlm.nih.gov/pubmed/9606144.

Gutheil, W. G. Statistical analysis of data pertaining to complex state systems by stepwise regression with reformulated parameters; application to spectroscopically monitored hemoglobin oxygen binding data. Biophysical chemistry 1998, 70, 185-202. http://www.ncbi.nlm.nih.gov/pubmed/9546196.

Gutheil, W. G. A simple chemical example of hierarchical thermodynamic interactions: the protonation equilibria of inorganic polyprotic acids. Biophysical chemistry 2000, 88, 35-45. http://www.ncbi.nlm.nih.gov/pubmed/11152274.

Gutheil, W. G. Application of hierarchical thermodynamic interactions to the protonation equilibria of organic polyprotic acids. Biophysical chemistry 2000, 88, 119-126. http://www.ncbi.nlm.nih.gov/pubmed/11152269.

Gutheil, W. G.; Stefanova, M. E.; Nicholas, R. A. Fluorescent coupled enzyme assays for D-alanine: application to penicillin-binding protein and vancomycin activity assays. Anal Biochem 2000, 287, 196-202. http://www.ncbi.nlm.nih.gov/pubmed/11112264.

Gutheil, W. G.; Xu, Q. N-to-C solid-phase peptide and peptide trifluoromethylketone synthesis using amino acid tert-butyl esters. Chemical & pharmaceutical bulletin 2002, 50, 688-691. http://www.ncbi.nlm.nih.gov/pubmed/12036033.

Stefanova, M. E.; Davies, C.; Nicholas, R. A.; Gutheil, W. G. pH, inhibitor, and substrate specificity studies on Escherichia coli penicillin-binding protein 5. Biochimica et biophysica acta 2002, 1597, 292-300. http://www.ncbi.nlm.nih.gov/pubmed/12044907.

Pechenov, A.; Stefanova, M. E.; Nicholas, R. A.; Peddi, S.; Gutheil, W. G. Potential transition state analogue inhibitors for the penicillin-binding proteins. Biochemistry 2003, 42, 579-588. http://www.ncbi.nlm.nih.gov/pubmed/12525187.

Stefanova, M. E.; Tomberg, J.; Olesky, M.; Holtje, J. V.; Gutheil, W. G.; Nicholas, R. A. Neisseria gonorrhoeae penicillin-binding protein 3 exhibits exceptionally high carboxypeptidase and beta-lactam binding activities. Biochemistry 2003, 42, 14614-14625. http://www.ncbi.nlm.nih.gov/pubmed/14661974.

Sasubilli, R.; Gutheil, W. G. General inverse solid-phase synthesis method for C-terminally modified peptide mimetics. Journal of combinatorial chemistry 2004, 6, 911-915. http://www.ncbi.nlm.nih.gov/pubmed/15530118.

Stefanova, M. E.; Tomberg, J.; Davies, C.; Nicholas, R. A.; Gutheil, W. G. Overexpression and enzymatic characterization of Neisseria gonorrhoeae penicillin-binding protein 4. European journal of biochemistry / FEBS 2004, 271, 23-32. http://www.ncbi.nlm.nih.gov/pubmed/14686916.

Nicola, G.; Peddi, S.; Stefanova, M.; Nicholas, R. A.; Gutheil, W. G.; Davies, C. Crystal structure of Escherichia coli penicillin-binding protein 5 bound to a tripeptide boronic acid inhibitor: a role for Ser-110 in deacylation. Biochemistry 2005, 44, 8207-8217. http://www.ncbi.nlm.nih.gov/pubmed/15938610.

Rai, A.; Gutheil, W. G. A Dde resin based strategy for inverse solid-phase synthesis of amino terminated peptides, peptide mimetics and protected peptide intermediates. Journal of peptide science : an official publication of the European Peptide Society 2005, 11, 69-73. http://www.ncbi.nlm.nih.gov/pubmed/15635629.

Peddi, S.; Nicholas, R. A.; Gutheil, W. G. Neisseria gonorrhoeae penicillin-binding protein 3 demonstrates a pronounced preference for N(epsilon)-acylated substrates. Biochemistry 2009, 48, 5731-5737. http://www.ncbi.nlm.nih.gov/pubmed/19413336.

Jamindar, D.; Gutheil, W. G. A liquid chromatography-tandem mass spectrometry assay for Marfey’s derivatives of L-Ala, D-Ala, and D-Ala-D-Ala: application to the in vivo confirmation of alanine racemase as the target of cycloserine in Escherichia coli. Anal Biochem 2010, 396, 1-7. http://www.ncbi.nlm.nih.gov/pubmed/19748470.

Stefanova, M.; Bobba, S.; Gutheil, W. G. A microtiter plate-based beta-lactam binding assay for inhibitors of high-molecular-mass penicillin-binding proteins. Anal Biochem 2010, 396, 164-166. http://www.ncbi.nlm.nih.gov/pubmed/19748471.

Bobba, S.; Gutheil, W. G. Multivariate geometrical analysis of catalytic residues in the penicillin-binding proteins. Int J Biochem Cell Biol 2011, 43, 1490-1499. http://www.ncbi.nlm.nih.gov/pubmed/21740978.

Bobba, S.; Ponnaluri, V. K.; Mukherji, M.; Gutheil, W. G. Microtiter plate-based assay for inhibitors of penicillin-binding protein 2a from methicillin-resistant Staphylococcus aureus. Antimicrob Agents Chemother 2011, 55, 2783-2787. http://www.ncbi.nlm.nih.gov/pubmed/21402836.

Putty, S.; Rai, A.; Jamindar, D.; Pagano, P.; Quinn, C. L.; Mima, T.; Schweizer, H. P.; Gutheil, W. G. Characterization of d-boroAla as a novel broad-spectrum antibacterial agent targeting d-Ala-d-Ala ligase. Chem Biol Drug Des 2011, 78, 757-763. http://www.ncbi.nlm.nih.gov/pubmed/21827632.

Bobba, S.; Resch, G. E.; Gutheil, W. G. A liquid chromatography-tandem mass spectrometry assay for detection and quantitation of the dipeptide Gly-Gln in rat brain. Anal Biochem 2012, 425, 145-150. http://www.ncbi.nlm.nih.gov/pubmed/22446498.

Putty, S.; Vemula, H.; Bobba, S.; Gutheil, W. G. A liquid chromatography-tandem mass spectrometry assay for d-Ala-d-Lac: a key intermediate for vancomycin resistance in vancomycin-resistant enterococci. Anal Biochem 2013, 442, 166-171. http://www.ncbi.nlm.nih.gov/pubmed/23938774.

Vemula, H.; Bobba, S.; Putty, S.; Barbara, J. E.; Gutheil, W. G. Ion-pairing LC-MS/MS-based quantification of UDP-linked intermediates in the S. aureus cell wall biosynthesis pathway. Anal Biochem 2014. http://www.ncbi.nlm.nih.gov/pubmed/25086364.

Rangarajan, P.; Subramaniam, D.; Paul, S.; Kwatra, D.; Palaniyandi, K.; Islam, S.; Harihar, S.; Ramalingam, S.; Gutheil, W.; Putty, S.; Pradhan, R.; Padhye, S.; Welch, D. R.; Anant, S.; Dhar, A. Crocetinic acid inhibits hedgehog signaling to inhibit pancreatic cancer stem cells. Oncotarget 2015, 6, 27661-27673. http://www.ncbi.nlm.nih.gov/pubmed/26317547.

Vemula, H.; Ayon, N. J.; Gutheil, W. G. Cytoplasmic peptidoglycan intermediate levels in Staphylococcus aureus. Biochimie 2016, 121, 72-78. http://www.ncbi.nlm.nih.gov/pubmed/26612730.