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Basic Research
on Bacteria
The Essential Frontier
Report on the American Society for Microbiology and
National Institutes of Health
Workshop on Basic Bacterial Research
The National Institutes of Health (NIH)
The Nationʼs Medical Research Agency, the NIH includes
27 Institutes and Centers and is a component of the U.
S. Department of Health and Human Services. It is the
primary federal agency for conducting and supporting
basic, clinical and translational medical research, and it
investigates the causes, treatments and cures for both
common and rare diseases. For more information about
NIH and its programs, visit www.nih.gov
The American Society for Microbiology (ASM)
The ASM is the largest single life science society,
composed of over 42,000 scientists and health professionals. The ASM's mission is to promote research and
research training in the microbiological sciences and to
assist communication between scientists, policy makers
and the public to improve health, economic well-being
and the environment. The ASM and its members work
to identify and support research efforts that can
address health and environmental problems.
February 2007
Cover and Interior Bacteria Images
Staphylococcus aureus—coccus prokaryote (MRSA bacterium)
Mycobacterium tuberculosis—rod prokaryote (bacterium)
E. coli (Escherichia coli)—dividing, hemorrhagic 0157:H7 strain.
© Dennis Kunkel Microscopy
www.denniskunkel.com
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Introduction
or many years the American Society for Microbiology (ASM) has been concerned about the need for
increasing basic research in bacteriology. This concern is based upon several premises, including:
1 the widespread perception that an adequate number of researchers in the U.S. in fields such as
bacterial physiology and genetics are not being trained,
2 the importance of basic knowledge of bacterial physiology and genetics in the biotechnology industry
and in applications including pathogenesis and biodefense,
3 the growing understanding of the impact of bacteria on human health, and on the development of chronic diseases.
To address these questions, the ASM and National Institutes of Health (NIH) jointly sponsored a workshop on Basic Research
in Bacteriology that was convened November 3-4, 2005 on the NIH campus in Bethesda, Maryland.
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Approach
he ASM-NIH workshop focused on scientific gaps and
opportunities for research on bacteria. In order to stimulate creative, goal-oriented interactions, the meeting integrated focused discussions within smaller working groups
and overarching sessions with entire group participation.
Participants in the two-day workshop included scientists
with a variety of research expertise, representatives of
industry, and representatives of federal agencies. Following
the meeting, the groupʼs Steering Committee prepared this
summary of the discussions and recommendations to
guide future research.
Goal: The workshop
participants focused on the
following discussion areas:
• What are the gaps in our knowledge, methodologies,
and information access that must be addressed?
What strategies would address these gaps?
• How has microbiological research at the basic and
applied levels been changed by technological advances
(e.g., genomics, imaging, and computation)? What new
opportunities have been revealed?
• How have these technological advances altered the perception of what problems are interesting and important?
What are the benefits and drawbacks to these changes?
• What factors have changed the marketplace for
microbiologists over the years and how? Is this picture
changing again? What are the roles of the research institutions in these shifts and how might they be influenced
in the future? What are the roles of the microbiological
societies in future shifts? What roles might the private
and public funding agencies play?
• What are the developments on the horizon that will affect
microbiological research in the next five years?
Basic Research on Bacteria The Essential Frontier
1
B
Overview
acteria and their phages are the oldest and most
abundant life forms on the planet. Bacteria have
co-evolved with us and are beneficial for human health. There
are over 10 times more bacteria in our bodies than there
are human cells, and this natural microbiota is essential
for proper development, nutrition, and resistance to disease.
However, we also live in an environment replete with bacteria
that can cause a wide variety of human diseases with
bacterial infections responsible for 25 percent of human
deaths globally, a number predicted to increase dramatically
with the growing crisis of antibiotic resistance. We understand very little about the interactions between bacteria
and the environment that influence the delicate ecological
equilibrium between humans and microbes and thereby
determine the balance between health and disease.
In addition to the bacteria that are in or on the human body,
bacteria influence humans in many other ways. Bacteria are
the dominant occupant and architect of our entire biosphere.
Bacteria sustain the metabolic cycles that are essential for all
life on earth. Bacterial metabolism sculpts our physical environment as well. Because they are ubiquitous and have such
diverse metabolic capabilities, bacteria influence essentially
all disciplines of science, including fields such as evolutionary
biology, ecology, immunology, cell and developmental biology, psychology, geology, chemistry, physics, climatology,
computer science, and engineering.
Bacteria are also instrumental for understanding fundamental life processes that are required by all organisms,
including central metabolism, replication, transcription,
translation, protein targeting, assembly and structure
of macromolecular complexes, protein folding, stress
responses, error correction mechanisms, signal transduction,
and developmental programs. These processes are more
easily characterized in model bacteria and their phages
than in other organisms because microbes provide such
tractable experimental systems. The large repertoire of
genetic and biochemical tools and data that have been
acquired from basic research on bacteria is crucial for
dissecting the complex metabolic and regulatory networks
that control these processes. This provides a launching
point for understanding the enormous diversity in the
bacterial world and facilitates the understanding of these
processes in eukaryotes.
2
Despite the broad impact of this field, basic research
on bacteria is at a crossroads. The research community
perceives that public funding for most areas of basic
research, including bacteriology, has leveled off and that
increased resources are being focused on infectious disease
research prompted in part by biodefense concerns. Coupled
to this, large multi-investigator projects have emerged as an
alternative to single investigator R01-type research projects.
These developments raise the questions: What is the relative
value of continued investment in basic research on bacteria,
and is there a disproportionate emphasis on large scientific
consortia at the expense of research by smaller groups?
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Evolving Priorities
esearch on bacteria and their phages has led to many
fundamental scientific discoveries. Initial support for this
research was justified in part because of the role of bacteria
in causing disease. With the advent of effective antibiotics it
seemed like the war on microbes had been won. Hence, for
several decades health-related research shifted to topics
like cancer, heart disease, and genetic diseases. Moreover,
developments in molecular biology arising from research on
bacteria made it possible to study many basic biological
processes in mammalian cells, eliminating the argument
that bacterial model systems were the only doorway to
eukaryotic molecular biology.
Meanwhile, the microbes demonstrated how rapidly they
could evolve new traits. Microbial resistance to antibiotics
developed faster than new antibiotics could be developed,
and the resistance spread throughout the microbial world.
The global expansion of food distribution networks facilitated
the rapid distribution of microbial pathogens. Simultaneously,
emerging microbial pathogens filled new ecological niches,
such as indwelling medical devices and the growing population of humans who are immunocompromised due to primary infections (including HIV) or due to therapies used to
treat chronic diseases. Furthermore, recent discoveries
have demonstrated that some diseases (including ulcers,
certain types of cancer, heart disease, etc.) that were previously believed to be caused by a genetic predisposition
or exposure to environmental toxins are actually caused by
microbes. This microbial offensive has summoned a
renewed counter-attack on microbial pathogens.
Meanwhile, new tools have become available that make it
possible to dissect the molecular basis of pathogenesis
both from the microbial and host perspectives. Recently,
having the complete DNA sequences of bacterial
pathogens has provided valuable insights into how microbial pathogens evolve and the extent of gene transfer
between pathogens. These advances have revealed new
ways to control infection, including the identification of
novel targets for antimicrobials and novel approaches for
vaccine development.
The value of basic research on bacteria has extended well
beyond infectious diseases. Research on bacteria led to
the elucidation of important concepts of molecular biology,
allowing developments in biotechnology that have yielded
tremendous benefits to many other aspects of human
health and well-being as well as providing new tools that
have facilitated our understanding of pathogenesis. With
the advent of new tools that allowed us to extend beyond
pure culture studies to identify bacteria in complex communities in the environment, it became clear that bacteria
have many roles in human health that were previously
unknown. These discoveries have opened important new
opportunities for research on bacteria. Although these new
technologies allow the rapid accumulation of data about
bacterial genes and gene expression, interpreting these
data relies on many basic aspects of bacterial genetics,
physiology, and ecology that are not yet well understood.
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Impact of New Technologies
ew approaches like genomics, transcriptomics, and
proteomics allow the identification of the entire genetic
complement of bacteria and which of these genes are turned
on under particular conditions. Comparative genomics led to
the discovery that gene exchange between bacteria is rampant and has dramatically influenced the acquisition of virulence, and had a major impact on our understanding of the
evolution of pathogenesis. However, interpretation of data
from these “omics” approaches relies on comparisons with
databases rather than direct functional assays. Thus, these
new approaches have not diminished the need for basic
research because a detailed understanding of microbial
physiology and genetics is essential to interpret and test the
resulting predictions. In fact, the ability of “omics” approaches
to generate a tremendous number of predictions greatly
increases the need for direct experimental tests based
upon genetics, biochemistry, and molecular biology.
Furthermore, the detailed characterization of the mechanisms of discrete pathways and reactions, and molecular
interactions that modulate these interactions is required for
understanding the integrated networks and for developing
new ways to modulate these processes for our purposes—
a major goal of systems biology.
Imaging is another technological advance that has provided useful insights into bacterial physiology and pathogenesis. Sensitive new approaches allow the visualization of
molecules within bacteria and bacteria within an infected
host. The applications of these approaches in bacterial
cell biology and ecology have only begun to be tapped.
Coupled with an understanding of bacterial physiology and
molecular biology, and the ability to genetically manipulate
these processes, will lead to new therapies that direct
active agents to particular sites in the host to combat
disease or stimulate health.
Because of sophisticated instrumentation requirements
and expense, efforts to develop these new technological
approaches are typically restricted to large groups of
scientists focused upon very specific problems. However,
interpreting the vast amount of data generated by these
new technologies and asking critical questions about what
it means typically relies on individual scientists with unique
expertise on a particular aspect of bacterial genetics, physiology, ecology, or molecular biology. To take optimal advantage
of the intellectual capital spread across academia and
industry, individual scientists should have access to the
facilities needed to perform such experiments and the
data generated from these experiments.
Basic Research on Bacteria The Essential Frontier
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Challenges and Opportunities
There are many remaining challenges and
corresponding opportunities.
• Gene function—We need improved approaches for the
rapid biochemical and genetic confirmation of predicted
functions, as well as improved computational methods
to accurately predict gene functions. A large number of
genes have unknown functions. What are the “unknown”
gene products doing?
• Annotation—Misannotation of genes, including the prob-
lem of derivative annotations, is a pervasive problem that
can result in misleading interpretations of genomic data.
• Metagenomics—Can we identify the roles of individual
microbes present in complex microbial communities such as
in the gut, in the oral cavity, on skin, etc.? To do so, we will
need better algorithms to analyze short-single reads,
assemble partial sequences, and recognize mechanisms
that distinguish which functions rely on consortia of microbes
vs. those that rely on individual microbes. This approach will
allow us to identify which microbes comprise our normal
biota and which others cause diseases as well as what diseases result from interactions between multiple microbes.
• Metabolomics—We need new ways to quantify metabolic
pools and flux through metabolic pathways to understand
how genetic information is realized through various functions, especially in differing host environments. Applications
of this technology include microbial forensics and enhanced
production of useful metabolites by industry.
• Systems biology—Because they are relatively simple and
well-characterized, bacteria provide an excellent model
system for systems biology. Multi-pronged studies on
bacteria should allow us to couple the dynamics of metabolic
pathways and regulatory networks to growth, adaptation,
behavior, and population and community dynamics. In
microbiology, the microbial community is ultimately the functioning unit of the system. Studying such interactions will
require close collaborations between microbiologists, computer scientists, mathematicians, physicists, and engineers.
4
• Evolution—Bacterial evolution is now an experimental
science that addresses the questions how and why.
Cumulative results to date have changed our understanding of the evolution and spread of antibiotic resistance
and emerging infectious diseases, but many fundamental
questions remain. How do new strains evolve? Where do
genetic islands come from? How does the acquisition and
loss of genes influence fitness in the host and the environment? Can we identify mechanisms that will lead to
the rapid identification of emerging infectious diseases?
Can we impede this process?
• Normal microbiota—Over the last few years, we have
developed a better understanding of the impact of our
natural microbiota on human health and disease, but
these studies have also raised many new questions. How
does natural microbial biota affect human development,
nutrition, and disease resistance? What is the role of
endogenous microbial biota in transfer of antibiotic resistance and virulence genes to potential pathogens? What
determines whether metabolites produced by natural
microbiota are used as beneficial nutrients or cause tissue
damage in the host? How does the natural microbiota
influence obesity, diabetes, and other chronic diseases?
• In vitro culture studies—Laboratory studies are invaluable
for studying bacterial physiology and genetics, facilitating
the identification of new imetabolites, the manipulation of
biochemical pathways for production of desired products,
etc. However, the vast majority of bacteria are still uncultured. How can we culture previously uncultured organisms to allow studies in lab?
• Transmission—We have learned many details of viru-
lence factors in a variety of bacteria, but we do not yet
understand many aspects of microbial ecology and
environmental adaptation that allow bacteria to survive in
the environment long enough to be transmitted to a new
host. Understanding this process will demand expertise in
microbial genetics, physiology, ecology, and mathematics.
• Antimicrobials—We desperately need innovative
approaches for the development of new classes of antibiotics (vs. simply modifying existing classes of antibiotics).
Can we develop new methods to slow the development of
antibiotic resistance? Are the current regimes of antibiotic
therapy optimal? What does ecology tell us about predicting and managing antibiotic effectiveness? Answering
these questions will demand collaborations between
microbiologists, chemists, and physicians.
• Immunity and tolerance—The human immune system
is constantly interacting with the thousands of bacterial
species comprising our natural microbiota. Understanding
how the natural microbiota communicates with the immune
system and how the immune system singles out harmful
microorganisms could lead to the development of drugs
that help the natural microbiota outcompete pathogens.
• Vaccines—We need new types of vaccines that provide
effective protective immunity and can be used in young
children and individuals with compromised immune systems. Needs include more effective mechanisms of vaccine delivery, vaccine targets that provide broad, longlasting immunity, and vaccine formulations that are stable
outside a narrow window of temperature and humidity
conditions. Development of these vaccines will require
integration of the fields of immunology, bacterial genetics,
comparative genomics, bioinformatics, and pathogenesis.
• Detection and identification—Rapid diagnostic tools to
allow identification of the disease-causing agent and its
resistance profile would make it possible to reduce the
use of broad-spectrum antibiotics and encourage the
development of targeted therapeutics that are less likely
to disrupt the natural microbiota.
• Chronic diseases—How do microbial infections stimulate
chronic diseases? Once we understand how, can we
develop new therapies to intervene and thus prevent this
process? These questions extend to dental microbiology
as well—for example, is there a relationship between periodontal disease and heart disease or premature births?
• Host-bacteria interactions—Genes that influence estab-
lishment of microbial populations may influence the ability of
bacteria to cause disease. Identifying the host and bacterial
genes that influence colonization and virulence, and studying the mechanics of the host-bacteria conversation, may
provide a novel approach for countering infections.
• Nanotechnology—To date most of our understanding of
structure and function of bacteria comes from studies on
populations of cells. However, averaging data from a
large number of cells obscures important processes that
occur with single cells. Similar arguments can be made
for single molecules. Understanding structure and function at the single cell and single molecule level has
important implications for nanotechnology. These questions are enticing a new generation of physicists into
microbiology, but they are often hindered by inadequate
understanding of bacterial physiology and genetics.
• Bacterial physiology and genetics—Solving the problems
described above demands a detailed understanding of
basic molecular processes that mediate growth, metabolism, and regulation in microbial cells. Although commonly
described in textbooks as if they are completely understood,
there are many important, unresolved questions about
basic bacterial genetics and physiology. For example,
although when bacteria enter a host they must adapt to the
increased temperature and osmolarity, we do not know how
genes are regulated in response to these physical changes.
In addition to insights on diseases, basic research on
bacteria also leads to discoveries that benefit human
health in other ways, including the development of new
tools for cloning and gene expression, the modulation of
metabolic pathways to overproduce useful end-products,
the use of microbes for nanotechnology, the use of microbes
for bioremediation of toxic waste and radioactivity, and the
use of microbes for alternative energy production.
Individual investigators with smaller lab groups provide the
expertise needed to deal with the tremendous diversity of
microbes, approaches, and scientific backgrounds required to
solve these varied problems. However, human resources will
need to be leveraged with shared access to sophisticated
equipment to carry out research at the increasingly complex
levels now possible. In addition, major efforts will be needed
to capture, analyze, and share the prodigious streams of data
already resulting from modern technological approaches.
Individual laboratories will need access to the most efficient
algorithms for such analyses, and access to tools that will
allow them to create their own knowledge environments.
Basic Research on Bacteria The Essential Frontier
5
M
Is Larger Better?
ost of the important discoveries in bacteriology have
come from seemingly distant corners of basic
research driven by individual investigators with small
research groups. Some examples of such important discoveries include the growth of microbes in biofilms, the
role of efflux systems in antibiotic resistance, the impact of
gene amplification on the development of antibiotic resistance, the role of metabolic pathways (e.g. the glyoxylate
shunt) on persistent infections, the role of normal flora in
animal health, and the role of phage in the spread of bacterial toxins. These discoveries did not come from research
efforts focused on a major initiative, but from research driven by basic scientific curiosity—a central premise of arguments by Vannavar Bush for the development of a federal
research enterprise. Like travel on back roads vs. expressways, both routes have important but different roles—the
expressway allows you to reach your destination faster but
the back roads are likely to reveal exciting vistas that are
hidden from the expressway. Likewise, research by smaller
research groups provides creative fodder for larger
focused research efforts aimed at countering infectious diseases, developing new antimicrobials, and detecting and
thwarting potential bioterrorism agents.
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T
Educational Needs
he fundamental concepts of bacterial physiology and
genetics are essential for both basic and translational
research. For example, an in-depth knowledge of bacterial
physiology and genetics is essential for effective development of new antibiotics, thwarting antibiotic resistance, construction of novel vaccines, and treatment of diseases
induced by asymptomatic infections. Bacteria are also vital
to fields like chemical biology, biophysics, geobiology, and
chemical engineering. However, newcomers from these
other fields often lack core knowledge of basic bacterial
physiology and genetics needed to integrate the disciplines.
Training in basic research on bacteria also provides the
skills needed in biotechnology, the pharmaceutical industry,
and clinical microbiology. Individualized research allows a
student to learn from mistakes and develop expertise in
trouble-shooting scientific problems in close collaboration
with a scientific mentor. However, there is concern in the
research community that basic research in the microbial
sciences has not flourished, resulting in fewer scientists
actively working in this area and fewer students trained to
respond to future microbial challenges.
There is a widespread perception among microbiologists
that enough scientists in bacterial physiology and genetics
are not being trained, seriously jeopardizing science,
medicine, and industry. There are several potential reasons
for this neglect. First, other than the widespread publicity
about the impact of antibiotic resistance, the community
has done a poor job of explaining the importance of bacteria
to the public. Because of this lack of awareness, there is
no forceful public lobby promoting research on bacteria. In
addition, this limits the exposure of young students to the
exciting opportunities in this field. Second, over the last
several decades there have been shifts in emphasis within
academic institutions that have led to a decline in department
support, hiring, and curriculum emphasis on microbiology;
in some cases microbiological research has been subsumed
within other departments, e.g., cell biology. Thus, despite
the critical importance of microbiology research and
education, many microbiology departments have
shrunk or disappeared.
B
Summary
asic research on bacteria has had significant impact on
many areas of science. This research has revealed
many fundamental features of all living cells, and has
produced novel tools that allow us to study previously inaccessible problems. Discoveries continue to be made using
model systems such as Escherichia coli and many other
microbes with unique properties. Making discoveries often
relies upon insights from studying the physiology and
genetics of model organisms coupled with newly developed experimental tools and creative ideas.
Thus, multiple perspectives provide the same answers to
the two questions posed in the overview—there is a need
for continued investment in basic research on bacteria, and
a continuing major role for research by individual research
groups. This raises the question: How can these objectives
be met in a time of limited resources? One approach would
be for the research community to tell its story in a manner
that will make the points in this document clear to the
public. Part of this story is a recognition of the significance
of bacteria in basic biology, genetics, chronic disease, and
nutrition as well as infectious disease. In addition, research
on topics like evolution and ecology has a direct impact on
the advancement of human health. Increased interagency
cooperation could promote progress in these critical areas.
“...research on topics like
evolution and ecology
has a direct impact on
the advancement of
human health.”
Basic research on bacteria is a critical long-term investment
for private and Federal research funding; it is vital to the
development of applications that improve human health and
well-being, and impacts our nationʼs economy. Applications
of basic research on bacteria are essential for medicine, the
pharmaceutical industry, biotechnology, bioremediation, and
alternative energy production. Developing these applications
will demand integration of many scientific disciplines. Given
the importance of this field for the Federal mission and the
interdisciplinary approaches required to exploit future
challenges and opportunities, there is a continued need
for basic research on bacteria.
Basic Research on Bacteria The Essential Frontier
7
Selected Readings
Altman et al. An open letter to Elias Zerhouni. Science, 307:1409 (2005).
Backhed F., Ley R., Sonnenburg J., Peterson D., Gordon J. “Host-bacterial mutualism in the human intestine.”
Science, 307: 1915-1920 (2005).
Bush V. Science: The Endless Frontier. United States Government Printing Office, Washington, DC (1945)
[available at http://www.nsf.gov/about/history/vbush1945.htm].
Fauci A. S., Zerhouni E. A. “NIH response to open letter.” Science, 308:49 (2005).
Kaiser J. “Microbiology: Détente declared on NIH biodefense funding.” Science, 308:938 (2005).
Maloy S., Schaechter M. “The era of microbiology: a Golden Phoenix.” International Microbiology, 9: 1-7 (2006).
National Research Council. Treating Infectious Diseases in a Microbial World: Report of Two Workshops
on Novel Antimicrobial Therapeutics. National Academies Press, Washington, DC (2006).
Overbye K., Barrett J. “Antibiotics: where did we go wrong?” Drug Discovery Today, 10: 45-52 (2005).
Schaechter M., Kolter R., Buckley M. Microbiology in the 21st Century: Where Are We and Where Are We Going?
American Academy of Microbiology, Washington, DC (2003).
Schlegel H. “Continuing opportunities for general microbiology.” Archives of Microbiology, 182: 105-108 (2004).
Sleator R., Hill C. “Patho-biotechnology: using bad bugs to do good things.” Current Opinion in Biotechnology,
17: 211-216 (2006).
“Applications of basic research on bacteria are
essential for medicine, the pharmaceutical
industry, biotechnology, bioremediation,
and alternative energy production.”
8
Ecology and Evolution
Appendix I
Some examples that demonstrate the
impact of basic research on bacteria are
listed below.
Molecular Biology
• Cloning (plasmid and phage vectors;
restriction enzymes)
• DNA sequencing
• PCR (Temperature stable polymerases)
• Protein overexpression (phage T7;
chaperones)
• Protein secretion
• Mutagenesis and DNA repair (discovered
in bacteria; including mismatch repair
which plays major role in certain cancers)
• Recombination (including site-specific
recombination systems used for genetic
engineering, and mechanisms of homologous recombination)
• Transposons (initial work in maize, but
molecular understanding from work in
bacteria)
Metabolism and Biochemistry
• Role of proton motive force in transport,
energy (substrate coupled proton fluxes
in bacteria)
• LacY as paradigm for secondary transporters (many now implicated in disease)
• Regulation of gene expression (via a
diversity of mechanisms, including gene
rearrangements, transcription, translation,
turnover, etc.—most discovered by
research in phage lambda and E. coli)
• Extent of microbial diversity (>99%
microbes uncultured; use of rRNA for
taxonomy)
• Evolution of new traits (acquisition of
pathogenesis islands via horizontal gene
transfer)
• Coordination of microbial populations
(quorum sensing)
• Growth of mixed microbial consortia as
biofilms
Medicine
• Discovery of antibiotics (streptomycin,
tetracyclines, vancomycin, bactricin, etc.)
• Antimetabolites (understanding of metabolic pathways led to improved therapies, e.g.
trimethoprim plus sulfa)
• Inhibitors of resistance mechanisms
(e.g. ß-lactamase inhibitors such as
clavulanic acid)
• Discovery of gyrase and other topoisomerases (led to quinolone antibiotics
such as ciprofloxacin, and anti-cancer
drugs such as etoposides that make
Type II topoisomerases toxic in rapidly
dividing human cells)
• Lipopolysaccharide structure (basis of
septic shock)
• Function of eukaryotic genes (comparative
genomics of CFTR and P-glycoprotein
sequences allowed prediction of their function based upon similarity to bacterial ABC
transporters)
• Live, attenuated vaccines (e.g. Aro
mutants of Salmonella enterica sv. Typhi,
required understanding of physiology)
In addition to the above discoveries that
emphasize the impact of microbiology prior
to the last decade, some recent examples
of discoveries resulting from basic
research on bacteria include the following.
Development of New Antibiotics
and Inhibitors
• Use of genomics to identify antibiotic
targets and vaccine candidates
• RNA and DNA aptamers as therapeutics
(resulting from work on phage T4,
aptamer-based treatments are currently
in clinical trials)
• Quorum sensing via homoserine lactones
(required for virulence of some bacteria,
inhibitors are being developed)
• Antibiotic resistance due to efflux pumps
(new inhibitors in trials)
• Integrase inhibitors (studies on transposition mechanisms in bacteria leading to
the understanding of the mechanism of
HIV integrase, and the appreciation that
this enzyme is a good target for drug
development; novel peptide antibiotics
that inhibit recombination)
• Antibiotic target interactions informing
modification of existing antibiotics (ribosome structure allows development of
new aminoglycosides; penicillin binding
proteins and mechanism of action of
penicillins; mechanism of resistance to
vancomycin; gyrase inhibitors, tRNA synthase inhibitor Mupirocin)
• Determined sites of action for pesticides
(including Roundup and the sulfonylurea
herbicides)
• Role of biofilms in antibiotic resistance and
persistence (targets for novel antibiotics;
tissues, implants, etc.)
• Role of stress responses in antibiotic
persistence and development of crossresistance
• Phage therapy
• Streptokinase as inhibitors of thrombosis
subsequent to myocardial infarction
Basic Research on Bacteria The Essential Frontier
9
Virulence Mechanisms
• Cytoskeleton rearrangements modulated
by bacteria (e.g. Listeria, Salmonella, etc.)
• Growth of animal pathogens in plants
(e.g. Salmonella)
• Role of metabolites in virulence (e.g.,
Mg++ as signal of macrophage infection,
relied upon basic studies of divalent ion
transport)
• Previously uncharacterized roles of host
functions in defense (e.g. research in
progress implicates Pon1 in host defense
in liver and spleen tissues)
Role of Bacteria in Chronic Disease
• Bacteria cause or contribute to particular
chronic diseases (opposing roles of
Helicobacter in stomach and esophageal
cancer; anaerobic consortia in periodontal
disease; periodontal bacteria in atherosclerosis; etc.)
• Role of periodontal bacteria in preterm
births (previously overlooked because
bacteria could not be cultivated)
• Role of glyoxylate shunt in persistent
infections by pathogens, including
bacteria and fungi (relied upon basic
understanding of pathway from work
in E. coli)
• Role of osmotic stress mechanisms (e.g.
glycyl betaine and proline accumulation)
in infectious disease (e.g. E. coli UTI,
Staphylococcus)
New Vaccines
• Use of minicells as vaccine delivery systems
• Edible vaccines (cheaper, do not need
refrigeration, relied upon Agobacterium
genetic engineering; e.g., hepatitis B
vaccine in potatoes successful in initial
human tests)
• Use of live attenuated Salmonella strains
to invoke mucosal immunity (relied upon
understanding of basic physiology)
• Use of Salmonella to deliver anti-cancer
treatments (relied upon understanding of
attachment/secretion systems)
• Role of normal flora in development of
host vascularization and immunity (e.g.
Bacteriodes)
Biotechnology (over 40% of
biotech products made in the
United States and European
Union use E. coli as a host)
• Identification of novel enzymes from
extremophiles and “metagenome
libraries”
• Nutrients in genetically engineered crops
(e.g. ß-catotene/Vitamin A in golden rice;
plant genetic engineering relied upon
basic research on Agobacterium)
• Overproduction of membrane proteins in
intracellular membranes of Rhodobacter
(e.g. cystic fibrosis receptor)
• Production of leucine-rich proteins for
chemotherapy (initially failed because
high level production leads to proteins
with norleucine substituted for methionine,
understanding of pathways gave the
solution)
• In vivo substitution of unusual amino
acids (increased stability of therapeutic
peptides; required basic understanding
translation)
• Tight on/off switches for gene expression
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Detection of Pathogens
• Rapid detection methods demand
understanding of extent of gene
exchange (e.g. phage-mediated mobility
of exotoxin genes, transfer of antibiotic
resistance, pathogenicity islands)
• Array technologies to identify microbes
and infections (required comparative
genomics)
• DNA-based rapid detection methods
based upon comparative genomics
• Protein-based detection of antibiotic
resistance and toxins (based upon
understanding physiology)
• Metabolic-based detection (forensic
microbiology relies on ability to trace
minute metabolites)
• Rapid breath tests for microbes (e.g.,
urease test for Helicobacter, others in
development)
• Identification of genetic determinants
responsible for changes in host specificity associated with emerging infectious
disease (relies on combination of genetics and comparative genomics)
Bioinformatics
• Correct annotation demands demonstration of functionality (direct genetic and
physiological tests in model organisms,
including bacteria and yeast; knowledge
still inadequate)
• Analysis of organisms that cannot
be cultured (e.g., causative agent
of syphilis)
Laurie Comstock, Ph.D.
Associate Professor of Medicine
Channing Laboratory
Brigham and Womenʼs Hospital
Harvard Medical School
Appendix II
ASM-NIH Workshop on Bacterial
Research participants.
Steering Committee
James Anderson, Ph.D.
Program Director, Division of Genetics
and Developmental Biology
National Institutes of General Medical Sciences
National Institutes of Health
Dennis M. Dixon, Ph.D.
Chief, Bacteriology and Mycology Branch
Division of Microbiology and Infectious Diseases
National Institute of Allergy
and Infectious Diseases
National Institutes of Health
Carol A. Nacy, Ph.D.
CEO, Sequella, Inc.
James M. Tiedje, Ph.D.
Professor, Center for Microbial Ecology
Michigan State University
General Meeting Participants
Jonathan Beckwith, Ph.D.
American Cancer Society Professor
Department of Microbiology and
Molecular Genetics
Harvard Medical School
Jorge Benach, Ph.D.
Professor, Center for
Infectious Diseases
Stony Brook University
Martin J. Blaser, M.D.
Chair, NYU Department of Medicine
New York University School
of Medicine
Richard H. Ebright, Ph.D.
Professor and Investigator
Howard Hughes Medical Institute at
Rutgers University
Claire M. Fraser-Liggett, Ph.D.
President and Director, TIGR
Nancy E. Freitag, Ph.D.
Associate Professor, Seattle Biomedical
Research Institute and
Department of Pathobiology & Microbiology,
University of Washington
Stanley Maloy, Ph.D.
Professor and Director
Center for Microbial Sciences
San Diego State University
Frederick M. Ausubel, Ph.D.
Professor of Genetics
Department of Molecular Biology
Massachusetts General Hospital
Harvard Medical School
J. Stephen Dumler, M.D.
Professor of Pathology
Division of Medical Microbiology,
Department of Pathology
The Johns Hopkins University
School of Medicine
George Georgiou, Ph.D.
Cockrell Regents Endowed
Chair in Engineering #9
Chemical Engineering, Biomedical
Engineering and Institute for Cell and
Molecular Biology
University of Texas at Austin
William R. Goldman, Ph.D.
Professor of Molecular Microbiology
Washington University School of Medicine
Jeffrey Gordon, M.D.
Professor and Director, Center for
Genome Sciences
Washington University
Everett Peter Greenberg, Ph.D.
Professor and Chair
Department of Microbiology
University of Washington
Eduardo A. Groisman, Ph.D.
Professor and Investigator
Howard Hughes Medical Institute at the
Washington University School of Medicine
G. Wesley Hatfield, Ph.D.
Professor, Department of Microbiology and
Molecular Genetics
University of California, Irvine
School of Medicine
Darren E. Higgins, Ph.D.
Associate Professor, Department of
Microbiology and Molecular Genetics
Harvard Medical School
Ann Hochschild, Ph.D.
Professor, Department of Microbiology
and Molecular Genetics
Harvard Medical School
William R. Jacobs, Jr., Ph.D.
Professor and Investigator
Howard Hughes Medical Institute at the
Albert Einstein College of Medicine
Samuel Kaplan, Ph.D.
Professor and Chair, Microbiology
and Molecular Genetics Department
University of Texas Health Science Center
Houston Medical School
Paul Keim, Ph.D.
Professor and Director
Pathogen Genomics
Translational Genomics
Research Institute (TGEN)
Northern Arizona University
Linda J. Kenney, Ph.D.
Associate Professor, Department of
Microbiology & Immunology
University of Illinois-Chicago
Roberto Kolter, Ph.D.
Professor, Microbiology and
Molecular Genetics
Harvard Medical School
Robert Landick, Ph.D.
Professor, Department of Bacteriology
University of Wisconsin-Madison
Robert A. LaRossa, Ph.D.
Research Fellow, Central Research &
Development
DuPont Company
Richard Lenski, Ph.D.
Hannah Distinguished Professor
Department of Microbiology &
Molecular Genetics
Michigan State University
Mary E. Lidstrom, Ph.D.
Associate Dean, Professor
University of Washington
Sheila A. Lukehart, Ph.D.
Professor of Medicine
University of Washington
Basic Research on Bacteria The Essential Frontier
11
Joe Lutkenhaus, Ph.D.
Professor, Department of Microbiology
University of Kansas Medical Center
Melvin Simon, Ph.D.
Division of Biology
California Institute of Technology
Jeffery F. Miller, Ph.D.
Professor and Chair, Department of
Microbiology, Immunology and Molecular
Genetics
UCLA
Magdalene So, Ph.D.
Professor and Chair, Department of
Molecular Microbiology & Immunology
Oregon Health & Science University
Charles P. Moran, Jr., Ph.D.
Professor, Department of
Microbiology & Immunology
Emory University School of Medicine
Shelley M. Payne, Ph.D.
Professor, Department of Molecular Genetics
and Microbiology
University of Texas at Austin
Malcolm E. Winkler, Ph.D.
Professor, Department of Biology
Indiana University Bloomington
Kit Pogliano, Ph.D.
Associate Professor
Biological Sciences
University of California, San Diego
Ryland Young, Ph.D.
Professor, Biochemistry/
Biophysics Department
Texas A&M University
Steve J. Projan, Ph.D.
Vice President, Biological Technologies
Wyeth
Federal Meeting Participants
Peg Riley, Ph.D.
Professor, Biology Department
University of Massachusetts Amherst
Martin Rosenberg, Ph.D.
Chief Scientific Officer
Promega Corporation
Lucia B. Rothman-Denes, Ph.D.
Professor, Department of Molecular
Genetics and Cell Biology
The University of Chicago
Molly Schmid, Ph.D.
Keck Graduate Institute
Olaf Schneewind, Ph.D., M.D.
Professor, Department of Microbiology
University of Chicago
David H. Sherman, B.S., M.S., Ph.D.
Professor, Life Sciences Institute
University of Michigan
Thomas J. Silhavy, Ph.D.
Warner Lambert-Parke Davis Professor
Molecular Biology Department
Lewis Thomas Labs
Princeton University
12
Gisela Storz, Ph.D.
Senior Investigator
Cell Biology and Metabolism Branch
National Institute of Child Health
and Human Development
National Institutes of Health
Patrick P. Dennis, Ph.D.
Program Director Molecular
and Cellular Biosciences
National Science Foundation
Daniel Drell, Ph.D.
Program Manager, Life Sciences
and Medical Sciences Division
Office of Biological and
Environmental Research
U.S. Department of Energy
Judith H. Greenberg, Ph.D.
Director, Genetics and
Developmental Biology
National Institutes of General Medical
Sciences/National Institutes of Health
Maria Giovanni, Ph.D.
Assistant Director for Microbial
Genomics and Advanced Technologies
National Institute of Allergy and
Infectious Diseases
National Institutes of Health
Maryanna P. Henkart, Ph.D.
Division Director Molecular
and Cellular Biosciences
National Science Foundation
Dennis Mangan, Ph.D.
Chief, Infectious Diseases
and Immunity Branch
National Institute of Child Health
and Human Development
National Institues of Health
Barbara Mulach, Ph.D.
Communications and
Policy Team Leader
National Institute of Allergy
and Infectious Diseases
National Institutes of Health
Ann Lichens-Park, Ph.D.
National Program Leader
Competitive Programs
U.S. Department of Agriculture
Sam Perdue, Ph.D.
Program Officer Bacteriology
and Mycology Branch
National Institute of Allergy
and Infectious Diseases
National Institutes of Health
N. Kent Peters, Ph.D.
Program Officer Bacteriology
and Mycology Branch
National Institute of Allergy
and Infectious Diseases
National Institutes of Health
Alexander Politis, Ph.D.
Chief, Infectious Diseases
and Microbiology IRG
Center for Scientific Review
National Institutes of Health
Norka Ruiz-Bravo, Ph.D.
Deputy Director for Extramural Research
National Institutes of Health
Michael Schaefer, Ph.D.
Program Officer Bacteriology
and Mycology Branch
National Institute of Allergy
and Infectious Diseases
National Institutes of Health
Diane Stassi, Ph.D.
Scientific Review Administrator
Center for Scientific Review
National Institutes of Health
Starting with bottom row, left to right:
Row 1: Linda J. Kenney, William R. Jacobs,
Jr., Michael Schaefer, Magdalene So,
Barbara Mulach
Row 2: Frederick M. Ausubel,
Stanley Maloy, Dennis Dixon,
Melvin Simon, Laurie Comstock,
William R. Goldman,
Nancy E. Freitag
Row 3: Roberto Kolter, Lucia B. RothmanDenes, Ann Hochschild,
Patrick P. Dennis,
J. Stephen Dumler
Row 4: George Georgiou, Ryland Young,
Richard Lenski, Shelley M. Payne,
Everett Peter Greenberg
Row 5: James M. Tiedje, James Anderson,
Gisela Storz, Robert A. LaRossa
Row 6: Thomas J. Silhavy, Sheila A. Lukehart,
Dennis Mangan, Mary E. Lidstrom
Row 7: Charles P. Moran, Diane Stassi,
Malcolm E. Winkler,
David H. Sherman, Robert Landick,
Ann Lichens-Park, Daniel Drell,
Peg Riley
Row 8: Jeffrey Gordon, Molly Schmid,
Kit Pogliano, Alexander Politis,
Carol A. Nacy, Richard H. Ebright
Row 9: N. Kent Peters, Claire M. FraserLiggett, Martin J. Blaser,
Joe Lutkenhaus
Row 10: Eduardo A. Groisman,
Olaf Schneewind, Jeffery F. Miller,
Darren E. Higgins,
Jonathan Beckwith
American Society for Microbiology
1752 N Street, NW
Washington, DC 20036
Tel: 202-737-3600
www.asm.org