GRAND VALLEY STATE UNIVERSITY
SABBATICAL LEAVE REQUEST APPLICATION FORM
1. Name: Roderick M. Morgan 2. Date employed by GVSU August 1997
3. College CLAS 4. Unit Biology Department
5. Semester(s) and year of latest sabbatical leave Fall 2003
6. Dates of Leave of Absence as faculty since the latest sabbatical leave N/A
7. Sabbatical leave is being requested for this year and semester(s)
Fall XX Winter XX Academic Year 2010-2011
8. Sabbatical Title Evaluation of Carboxylic Amides as Antibacterial Agents
9. Are grants, fellowships, or other financial support expected during the sabbatical leave? Specify.
Yes. I plan on submitting grant proposals to the The Michigan Initiative for Innovation and
Entrepreneurship (MIIE) Technology Commercialization Fund through the State of Michigan and the
Grand Valley Research Core (a Grand Rapids area funding group) in the Spring of 2010.
10. Is acceptance of a sabbatical award dependent on your receiving some additional support?
Specify. Yes, I need to receive some funding for the entire year’s proposal
11. Where will the sabbatical work be done? GVSU, 207a Padnos Hall
12. In accord with the Sabbatical Policy as stated in Chapter 4, 2.30.4D of the Administrative Manual
(see also Chapter 3, Section 3.04.C.5.d, Chapter 3, Section 3.04.E.6,7 and Chapter 4, Section 4.02
item 2.30.4.D, Faculty Handbook), I agree to submit a written account of my activities and a
financial statement by the end of the term following my leave. I will remain at Grand Valley State
University for at least one year after completion of my leave regardless of the length of the
sabbatical.
____________________________________________________________________________________
Signature of Applicant Date
This sabbatical request has been reviewed by:
(approval, disapproval, or approval as modified)
Unit Date
(approval, disapproval, or approval as modified)
Applicant's Unit Head Date
(approval, disapproval, or approval as modified)
Chairperson, College Personnel Committee Date
(approval, disapproval, or approval as modified)
Dean Date
(approval, disapproval, or approval as modified)
Provost Date
Morgan Sabbatical for Fall 10/Winter 11 Sabbatical Form
SABBATICAL APPLICATION FORM FOR PREPARATION OF SABBATICAL LEAVE REQUESTS
A. This application is to be submitted to the College Dean no later than November 1 of the academic year
preceding the academic year of leave. Unit review must therefore be complete before November 1.
B. Please type using 12 point font (either single or double space) a maximum of 10 pages for the narrative.
Supporting letters and documents may be placed in an appendix. Use the “Sabbatical Leave Request
Application Form” as the cover page to your proposal. Your Dean's office will tell you how many copies are
needed.
C. Using this form, fill in the expandable gray boxes (Numbers 1-8) with narrative text. Please follow the
instructions given under each heading, and be sure to complete each field.
1. Descriptive title of your project.
Evaluation of Carboxylic Amides as Antibacterial Agents
2. Goals and objectives.
Proposals must have a clear conceptual focus. Be certain that the conditions and criteria for sabbatical
leave as stated in the Administrative Manual, chapter 4, section 2.30.4.D), have been addressed. Proposals
should be specific about the academic purpose of the leave. In particular, a proposal should conform to
some or all of the following:
a) a planned effort to retrain professionally (with approval of the chair);
b) development of new capabilities for teaching or research;
c) a synthesis or development of prior effort or experiences;
d) concern with a significant problem, area, or issue in the field of study;
e) promise of a significant contribution to the subject under study or problem undertaken;
f) practice of skills or application of research result which deepens or extends the applicant’s
professional capabilities.
Goal 1 – I plan to examine the antibacterial properties of carboxylic amide derivatives.
Objective #1: Identify chemically synthesized derivatives of carboxylic amides that confer
antibacterial activity in the presence of human serum protein.
Objective #2: Expand the known target organisms for active derivatives.
Sabbatical Emphasis area: a synthesis or development of prior effort or experiences;
concern with a significant problem, area, or issue in the field of study; promise of a significant
contribution to the subject under study or problem undertaken;
Goal 2 – Begin synthesis of previous research results from studies concerning the antimicrobial activity of
carboxylic amides for manuscript preparation.
Objective #1: Organize results and data obtained during the past 2 years concerning our discovery
that certain carboxylic amides have antibacterial activity for publication.
Sabbatical Emphasis area: a synthesis or development of prior effort or experiences
3. Evidence of preparation.
Describe academic preparation that contributes to feasibility of the project, placing the planned activity in
the context of your field. There shall be a thorough attempt by the proposer to search the literature and
to place the planned activity in the context of that literature. This may take the form of literature
citations, consultations, and indication of previous work in the field. If a book is being written, append
an outline or table of contents to demonstrate that groundwork has been laid.
Morgan Sabbatical for Fall 10/Winter 11 Sabbatical Form
Despite the extensive use of antibiotics and vaccination programs,
infectious diseases continue to be a leading cause of morbidity and mortality
worldwide (1). Deaths from hospital-acquired infections in the US were
13,300 in 1992, compared with around 100,000 today (6). This shows a
700% increase over the preceding decade, equivalent to a 20% annual
growth during that time. Widespread antibiotic resistance, the emergence of
new pathogens in addition to the resurgence of old ones, and the lack of
effective new therapeutics exacerbate the problems. Bacterial infections of
particular concern include methicillin resistant Staphylococcus aureus
(MRSA), vancomycin resistance enterococci (VRE) and multi- drug resistant
tuberculosis (XDR).
Development of new drugs that combat or circumvent antibiotic resistance mechanisms is pivotal for human
health and well-being.
Current Antibiotics: Although, today's armory of antibiotics is
substantially reliant on compounds that have been used for many
years, there is increasing dependency on a small number of
drugs, some of which have only recently entered the market.
Four antibiotic classes (beta lactams, quinolones,
aminoglycosides and macrolides), against which there is rapidly
developing resistance, represent almost three-quarters of all
currently available drugs (5). While these remain important
first-line antibiotics, others such as Vancomycin and more
recently Zyvox (Pfizer), Tigecycline (Wyeth) and Daptomycin
(Cubist) are important in the treatment of some difficult infections.
Unfortunately, resistance is developing against these agents as
well (8).
Development Pipelines: The current development pipeline at major pharmaceutical and biotechnology
companies shows substantial reliance on anti-bacterial classes that are similar to those already in use and against
which resistance is accelerating. For example, currently there are around 370 anti-bacterial compounds in the
development pipeline, 60% of which are at the pre-clinical stage (7). While a number of promising
developmental compounds are in late-stage development such as Pfizer's Ramoplanin and Glasko Smith Kline's
Retapamulin, three quarters of late stage candidates are based on or closely related to existing fully launched
drugs. Of the 315 candidate anti-bacterials at the pre-clinical to Phase II stages, 40% are closely related to
established classes of anti-bacterials (7).
History of antibiotic work at GVSU: A novel class of potentially potent antibacterial substances has been
discovered in a collaborative project between the Chemistry and Biology departments at Grand Valley State
University (GVSU). These compounds do not rely on currently identified, developed, and accepted antibiotic
chemical structure. Rather, they seem to have a proposed mechanism of action that is significantly different
from currently understood mechanistic pathways for treatment of infections, and are readily synthesized,
avoiding complex, stereoselective, multi-step chemical synthesis.
We began screening compounds for antimicrobial activity in the summer of 2007 through the support of a
Student Summer Scholar award. Our initial discovery was made when compounds synthesized as potential
anticancer telomerase inhibitors were submitted to standard microbiological analysis designed to measure
Morgan Sabbatical for Fall 10/Winter 11 Sabbatical Form
antimicrobial activity. The known telomerase inhibitor BIBR1532, {(E)-2-(3-(naphthalene-2-yl) but-2enamido)
benzoic acid, was also tested since it was the standard to which the potential telomerase inhibitors were to be
compared. [US Patent 6362210, COM; Assignee: Boehringer Ingelheim Pharma KG; issue date March 26,
2002] Of considerable interest was the discovery that BIBR1532 demonstrated significant antimicrobial
activity against a group of microorganisms categorized as Gram-positive bacteria. Furthermore, the minimum
inhibitory concentrations (MICs) of BIBR1532 against these bacteria are equivalent to existing clinically useful
antibiotics (the MICs range from 2- 78 ug/ml, depending on the organism being tested). In subsequent in-vitro
tests, BIBR1532 showed activity against methicillin-resistant Staphylococcus aureus (MRSA) and vancomycin
resistant enterococci (VRE). The antibacterial activity against MRSA and VRE strains of bacteria is extremely
promising as it demonstrates the ability of BIBR 1532 to inhibit microbial growth in organisms with resistance
to commonly prescribed antibiotics.
In February of 2008, the university submitted a provisional patent on our behalf involving the use of BIBR 1532
as an antibiotic. The provisional patent was converted to a full patent application in March of 2009. During the
process of screening BIBR 1532 derivates, we discovered a second class of compounds distinct enough to
warrant a second provisional patent application. To further study these potentially new antibiotics, we applied
for and received a one-year grant from The Michigan Initiative for Innovation and Entrepreneurship (MIIE)
Technology Commercialization Fund through the State of Michigan. The funds allowed us to take giant steps
in analyzing the biological activity of these compounds, but the funding period ended in August of 2009. These
external funds allowed us to contract work with two biotechnology companies in Kalamazoo, MI that specialize
in antimicrobial testing; Micromyx, LLC, and Ceetox, Inc. In summary, our advancements from the grant
period include: 1.) gaining insight into the mechanism of action for both compounds, 2.) discovering the
frequency of resistance against the compounds is extremely low, 3.) greatly expanding the known bacterial
targets for these compounds, 4.) discovering that the compounds inhibit the growth of bacteria through
bacteriostatic activity (ie. inhibition of growth as opposed to lysis of the cells), and 5.) discovering the
compounds have minimal toxic effects on human cells in vitro. During this time frame, we were able to screen
>70 derivatives. Sixty of the compounds demonstrated antibacterial activity and 18 of which were more
thoroughly analyzed. We have only discovered one negative aspect of our compounds; they bind strongly to
proteins found in the serum portion of human blood. Unfortunately, the binding of the compounds to human
serum proteins reduces the effectiveness of the compounds in vivo, hence we need to modify the compounds to
reduce this unwanted binding. We believe the binding occurs on the carboxylic acid group and we plan to
create and test a number of compounds to alleviate the serum protein binding problem. We have had a fruitful 2
years with regard to this research and to date, this work has involved nine students, resulting in three external
presentations and four internal presentations. We are confident we can make progress to developing these new
classes of antibiotics and plan to include students in this process.
4. Project Plan.
Describe the sabbatical project. Show how that plan relates to its goals and objectives.
Goal 1 – I plan to examine the antibacterial properties of carboxylic amide derivatives.
Objective #1: Identify chemically synthesized derivatives of carboxylic amides that confer
antibacterial activity in the presence of human serum protein.
Objective #2: Expand the known target organisms for active derivatives.
Screening the antibacterial activity of synthesized compounds is a very directed endeavor that relies heavily on
“trial and error” examinations. The typical process involves testing a few compounds to obtain relative strength
of activity and then discussing and creating related compounds based on this activity. This results in
incremental increases in antibacterial activity with each successive chemical derivative. The “trick” is to retain
antibacterial activity while reducing protein binding. Because the creation of compounds is heavily dependent
Morgan Sabbatical for Fall 10/Winter 11 Sabbatical Form
on results from the microbiological analysis, we cannot create 75 compounds first and then test them all; it is
extremely inefficient and expensive. Providing feedback to the chemists allows for a more systematic approach
to the creation of the chemical derivatives.
Chemical synthesis: The chemical synthesis will occur in the laboratory of Dr. Robert Smart, here at GVSU
and will be performed by Dr. Smart and Dr. William Schroeder (an Adjunct Professor of Chemistry) as well as
undergraduate students. The base amid acids will be synthesized in 25 gram scale. These compounds will be
purified by crystallization and characterized using NMR and IR spectroscopy. These compounds will serve as
the base compounds for all subsequent compounds synthesized for this study.
The carboxylic acid functionality on the base compounds have shown to bind to protein in serum (4). We will
react this site with a variety of amino acid derivatives to convert the acid into a new amide bond (see chemical
structures below). This will shift the carboxylic acid functionality away from the aromatic ring. Our hope is
that the activity of the antibiotic will remain unchanged but the problem of serum binding may be overcome.
We envision that we should be able to make 1 to 3 compounds a week for testing. As with our base
compounds, we will need to purify and characterize the final product before testing can occur. The compounds
will be dissolved at a concentration of 10 mg/ml in 20% DMSO. We plan to test 70-100 compounds over the
course of the sabbatical.
O O
NH O Modif y Here NH O Modif y Here
OH Cl OH
CN CN
Antibacterial evaluation: The antimicrobial work will be performed in my designated lab space at GVSU with
the aid of two undergraduate students. Standard techniques will be used to evaluate the antibacterial properties
of the compounds following the recommendations in the Clinical and Laboratory Standards Institute. We will
utilize two methods to test the bacterial inhibition properties of the compounds using standardized Mueller-
Hinton II Broth as the growth medium (2,3). The first test is termed a disk diffusion test and this test is
performed by placing a paper disk on top of “lawns” of overnight cultures of organisms. Ten ul of the test
compounds will be added to the disks and the plates will then be allowed to grow for 18-24 hours. If the
compound has antibacterial properties, a zone of inhibition will be observed and measured. The second test is
used to determine the minimum inhibitory concentration (MIC) of the compound against a specific bacterium.
To perform the MIC test, the compound is diluted in ½ step increments and then added to growing cultures of
bacteria (2,3 ). The MIC is simply the lowest concentration that inhibits growth of the bacteria. Our target
MICs range from 2-64 ug/ml. The MIC assay is performed in triplicate using 96-well microdilution plates with
one dilution series acting as the negative control (it does not receive an inoculum of bacteria). Once target
compounds have been identified (ie. those that produce a good antibacterial effect), the human serum binding
properties will be evaluated. To do the human serum binding assay, MIC dilutions are prepared as described
above, except that pooled human serum will be added to the dilutions to achieve a final concentration of 2.5%
or 10%. Again, each dilution series will be done in triplicate with one series acting as the negative control. If
human serum binds and inactivates the antibacterial properties of our compounds, a “shift” in the MIC will
occur, meaning that more of the compound will be required to have the same inhibitory effect against the target
bacteria. We are searching for compounds that do not bind to human serum and thus would not observe an
upward shift in the MIC in the human serum assay. As a final step in the microbiological analysis of the
compounds, any derivates that retain normal activity in the presence of human serum will be tested for activity
against a variety of Clostridium species. Clostridium infections can cause life-threatening diarrhea and can be
Morgan Sabbatical for Fall 10/Winter 11 Sabbatical Form
acquired in hospitals and nursing homes. Through our past efforts, we know Clostridium species are extremely
sensitive to our two classes of drugs and we want to verify that any new derivates we create still retain good
activity against them. Unfortunately, Clostridium species are very difficult to grow at GVSU (we simply lack
the appropriate equipment, which would cost ~$20,000 to obtain) and we would contract out to Micromyx, LLC
to perform the analysis. Micromyx is a biotechnology company located in Kalamazoo and specializes in
evaluating compounds for antimicrobial activity. We have used their services extensively in the past and have
built a good working relationship.
By late winter/early spring of 2011 we hope to have identified good candidate compounds and plan to test them
for toxicity affects in vitro. This work would be done at Ceetox, Inc. in Kalamazoo. Most of the work
described above can be performed with minimal funding, however, if we wish to test for toxicity, we will need a
more substantial funding source, ie. the external funding agencies mentioned above.
Goal 2 – Begin synthesis of previous research results from studies concerning the antimicrobial activity of
carboxylic amides for manuscript preparation.
Objective #1: Organize results and data obtained during the past 2 years concerning our discovery
that certain carboxylic amides have antibacterial activity for publication.
The antibacterial testing of the chemical compounds will have periods of great effort, involving the actual
testing and feedback to the chemical design team. There will also be periods of low effort, involving waiting on
the new synthesized compounds. During these low times, the year sabbatical leave will allow me to spend
much needed time preparing our results for manuscript publication. Because of my administrative and teaching
commitments over the past two years, I have lacked the necessary time to synthesize an appropriate publication
based on our two year effort. Secondly, because of patent restrictions, we have been limited to what can be
presented and how it can be presented. With the appropriate patent protection now in place we have been given
the “green-light” to proceed with a more thorough publication.
Reference Cited:
1.) Baltz, R. Antimicrobials from Actinomycetes: Back to the Future. Microbe 2007: 125-131.
2.) Clinical and Laboratory Standards Institute. Methods for Dilution Antimicrobial Susceptibility Tests for
Bacteria That Grow Aerobically; Approved Standard—Seventh Edition. Clinical and Laboratory Standards
Institute document M7-A7 [ISBN 1-56238-587-9]. Clinical and Laboratory Standards Institute, 940 West
Valley Road, Suite 1400, Wayne, Pennsylvania 19087-1898 USA, 2006.
3.) Clinical and Laboratory Standards Institute. Performance Standards for Antimicrobial Susceptibility
Testing; Eighteenth Informational Supplement. CLSI document M100-S18 [ISBN 1-56238-653-0]. Clinical and
Laboratory Standards Institute, 940 West Valley Road, Suite 1400, Wayne, Pennsylvania 19087-1898 USA,
2008.
4.) Hauel, N., Priepke, H., Damm, K., Schnapp, A Carboxylic Acid Amides, Pharmaceutical Compositions Containing
These Compounds And Their Use. US Patent 6362210, Assignee: Boehringer Ingelheim Pharma KG Issue Date March
26, 2002.
5.) Hawkey P.M. The growing burden of antimicrobial resistance. J Antimicrob Chemother. 2008; 62:1-9.
6.) Kollef, M.H. and V.J. Fraser. Antibiotic Resistance in the Intensive Care Unit
Ann Intern Med. 2001;134:298-314.
Morgan Sabbatical for Fall 10/Winter 11 Sabbatical Form
7.) Nathan, C. Antibiotics at the crossroads. Nature. 2004: 431: 899-902.
8.) Walsh, C. Molecular mechanisms that confer antibacterial drug resistance
Nature. 2000: 406:775-781.
5. Timetable.
Indicate estimated dates for each of the significant steps in the project plan. Be as specific as possible.
Include an explanation showing whether the project can be completed in the time available. If the
sabbatical leave is being used to begin a longer term project, state when you expect the whole activity to
be completed.*
Month Activity
Spring/Summer 2010 Submit grant proposal to the MIIE and Grand Valley
Research Core
August 2010-December Continue to test compounds and provide feedback for
2010 modifications
January 2011 Work with Micromyx to test best of class for MIC
activity, serum binding, and target range. Use this
information for modifications to compounds to improve
activity.
January 2011-April 2011 Create and test compounds based on Micromyx results.
February 2011-April 2011 If results from Micromyx results are sufficient, move to
in vitro toxicity testing with Ceetox, Inc.
September 2010-April 2011 Ongoing preparation of results for publication
6. Benefit to one’s own or other units.
A clear relationship between the proposed sabbatical leave and a proposer’s academic unit shall be
demonstrated. If your project is to benefit a unit other than your home unit, describe that situation.
Attach signed, written verification of that benefit from the head of that other unit.
This sabbatical proposal aligns with the Biology Department Strategic Plan in that it helps meet two Vision
ideals and two Long-Term Goals:
Relevant Vision Ideals:
“We recognize that student involvement in original research is a critical component to a first-rate biology
program and we aspire to provide the means for all of our undergraduates to participate in research.
We recognize that a diverse faculty engaged in their areas of expertise and responsive to the needs of our
students, colleagues and community are necessary for a first-rate program. We aspire to support our faculty
such that they may perform this role.”
Morgan Sabbatical for Fall 10/Winter 11 Sabbatical Form
Relevant Long-term Goals:
1. To maintain and enhance resources, space, and logistics which facilitate faculty professional
development in teaching, research, and service, and provides opportunities for undergraduate and
graduate research.
2. To generate and sustain mechanisms that foster vibrancy, engagement, and curiosity among students and
a faculty which continues to grow intellectually.
Additionally, we fully expect to publish at least one manuscript and two external presentations (ideally given by
undergrads) based on the research results; keeping in mind any restrictions based on patent potential.
7. Arrangements with people or other institutions.
If the project requires collaboration with other institutions or persons, describe the collaboration and
provide evidence that the institutions or persons involved agree with the arrangements.** If not, please
indicate that no collaboration is necessary or planned. For books, indicate interest of potential publisher
if available. You may append correspondence.
Much of the work is dependent on our ability to modify and create compounds. This work will be done in
the laboratory of Dr. Robert Smart, here at GVSU. The primary scientists involved in the synthesis
will be Dr. William Schroeder (Adjunct Professor) and Dr. Jason Fisk (Visiting Assistant Professor).
I have attached a letter from Dr. Smart indicating his support of the project
8. Other relevant information.
9. Appendices.
a. Attach copies of previous sabbatical reports in the Appendix.
b. Attach a copy of your curriculum vitae in the appendix.
This should be current and complete. Include a list of publications, exhibitions, performances, and
productions.
c. Attach letters of support or other supporting documentation.
D. If modification is made after a step in the review process but prior to the College Personnel Committee
recommendation, incorporate the modification into the appropriate section of the final proposal as opposed to
appending pages. If changes are proposed after the final approval but before or during the sabbatical period,
prior consultation with the chair of the unit should occur and a new formal plan document must be approved
by the Dean and the Provost before implementation of the proposed plan.
E. Final Report. Each faculty member returning from sabbatical leave will provide a written account of the
sabbatical activities and accomplishments and deposit copies with his/her appointing officer and unit head, the
Morgan Sabbatical for Fall 10/Winter 11 Sabbatical Form
Provost, the President, the Research and Development Center, and the library. The report shall be filed no later
than the end of the first semester after return to campus and shall include an account of the financial
remuneration received during the sabbatical leave. Failure to complete the approved sabbatical project, submit a
final report or participate in dissemination of sabbatical work may negatively affect an annual salary adjustment
and decisions on future sabbatical proposals.
________________
*In such a case, your sabbatical report is to be made as scheduled by the policy stated in the Administrative Manual
even if the entire project is unfinished. Report on whatever was accomplished during the sabbatical leave.
**If there is a possibility of creating Intellectual Property during a sabbatical and you are involved in external
collaboration with another university, business or organization, it is important to review the GVSU and
collaborating institution Intellectual Property Policy (IPP) prior to initiating work activities. For support in the IPP
review contact GVSU legal counsel.
Revised 6/06
Morgan Sabbatical for Fall 10/Winter 11 Sabbatical Form
Morgan Sabbatical for Fall 10/Winter 11 Sabbatical Form