Speakers

Keynote Address and Careers Panel Speaker

Dr. Virginia Miller

Dr. Virginia Miller

University of North Carolina

Yersinia pestis– models, bottlenecks and dogma

I have nearly thirty-five years of experience working in the area of molecular genetic analysis of bacterial pathogenesis (Yersinia pestis, Yersinia enterocolitica, Klebsiella, Salmonella, Vibrio cholerae), and thirty years experience with the pathogenic yersiniae (Y. pestis, Y. enterocolitica and Y. pseudotuberculosis) in particular. Over the years we have been leaders in bringing observations made in the laboratory using in vitro models (including tissue culture models of infection) to in vivo (mouse) models of infection in order to better understand host-pathogen interactions. Much of our effort has focused on the identification and characterization of virulence determinants, their role in pathogenesis, mechanism of action, and regulation of expression. We also have expended considerable effort in our lab over the years to using the best available animal models at the time in order to mimic natural infection as closely as possible. I have mentored many undergraduates, graduate students (16) and postdoctoral fellows (21) over the years. Most of these have gone on to productive careers in science including as faculty at leading institutions in the US (e.g. New York University, UCLA, UC Davis, University of Louisville).

Invasion factors of Yersinia enterocolitica. This project began in the mid 1980s and at the time the use of tissue culture assays to identify and characterize putative virulence phenotypes and determinants was in its infancy. When I began this work the Falkow lab had just identified Invasin from Y. pseudotuberculosis as protein that confers the ability to invade tissue culture cells and they proposed this was important for translocation of the pathogen across the intestinal epithelium. Subsequently I initiated a similar screen for invasion determinants of Y. enterocolitica (a related enteropathogen) and was able to: (a) show Y. enterocolitica encodes multiple invasion determinants (Invasion, Ail, YadA), (b) we were the first to show in an animal infection that Invasin is needed for efficient establishment of infection in Peyer’s Patches (i.e. penetration of the epithelium) and that the other invasion factors also contribute to pathogenesis, (c) show that ail was a potential diagnostic marker for pathogenic strains, (d) identify key regions of Ail important for cell binding and serum resistance.

RovA, global regulator of virulence in Yersiniae. Given the importance of Invasin for invasion of host cells and virulence we became interested in understanding when and where it was expressed as well as the regulatory factors involved. We were able to show that inv expression is regulated by temperature and pH and that it is expressed during infection. We subsequently identified RovA as a key regulator of inv expression and showed that it acts as a derepressor of the inv promoter by competing for binding at the promoter with an H-NS/YmoA complex. Furthermore we found that RovA is a global regulator of virulence (not just inv) in Y. enterocolitica and Y. pestis. Interestingly, the set of genes regulated by RovA in these two Yersinia species are quite different and analysis of these sets indicates RovA primarily regulates horizontally acquired genes (which differ between the two species); this is consistent with a mechanism of derepression of H-NS repressed genes as H-NS appears to preferentially repress expression of horizontally acquired genes.

Identification of invasion genes and their regulation in Salmonella. As with Yersinia the identification of invasion factors for Salmonella was thought to be important for understanding pathogenesis, and the use of tissue culture assays beginning in the mid-1980s brought an explosion of interest in this topic. Early results indicated that unlike Yersinia, a single gene in Salmonella is not sufficient to confer invasion. Thus, we used a genetic approach to identify genes involved in invasion and subsequently also studied the complex regulation of those genes. This work along with that of many other investigators subsequently determined that invasion by Salmonella is dependent on a type 3 secretion system (T3SS) - specifically the SPI1 T3SS. We were the first to determine that the AraC-like transcriptional regulator InvF must interact with SicA, a T3SS chaperone, in order to activate expression of SPI1 effectors. A similar type of mechanism has been shown in Shigella as well as for the chromosomal T3SS of Y. enterocolitica. This is an elegant mechanism for upregulating effector expression only under conditions when the secretion apparatus is active.

Pathogenesis studies using fully virulent Yersinia pestis. During the mid-2000s there was renewed interest in understanding the pathogenesis of Y. pestis. While much was known about the molecular mechanisms of the plasmid encoded T3SS (Ysc/Yop) little was known about how these and the few other identified virulence determinants actually contributed to pathogenesis. Furthermore, often the infection studies used avirulent strains in order to avoid the need for using BSL3 containment. Subsequent studies from our laboratory and others reinforced the importance of using fully virulent strains in order to understand how various host and bacterial factors contribute to virulence, and reinforced the importance of using appropriate doses and models of infection. Using a fully virulent strain and an intradermal model of infection with a low inoculum (analogous to the flea) we recently demonstrated (a) that there is an early bottleneck to establishing infection in the lymph node (LN), (b) that bacterial dissemination to LN can occur via lymphatics as free bacteria, and (c) that the subcutaneous inoculation route shows significant differences from the more natural intradermal route. In other studies we showed that the omptin protease Pla plays a role in pneumonic plague and we identified the autotransporter YapE as a virulence determinant whose function is dependent on cleavage by Pla.

ToxR, the global virulence regulator of Vibrio cholerae. In the early 1980s molecular genetic approaches were just beginning to be applied to studies of microbial pathogenesis. During this time, as a graduate student, I identified the master regulator of cholera toxin gene expression, ToxR. This was the first virulence gene regulator to be cloned and sequenced. Our subsequent studies demonstrated that ToxR is an usual transcriptional regulator in that it is an inner membrane protein. We also showed that it was a global regulator of virulence and it was studies of the ToxR regulon that led to the identification of the key colonization factor of V. cholerae - Tcp pili.

Career Panels Speakers

Karen Bush, PhD

Karen Bush, PhD

Dr. Bush received her PhD in Biochemistry from Indiana University and was involved with pharmaceutical research from 1973 to 2009, primarily working in the area of antibiotic drug discovery and development at Squibb (Bristol-Myers Squibb), Lederle, Astra and Johnson & Johnson Pharmaceutical Research & Development. Her basic research work involved the characterization of antibiotic (beta-lactam) resistance mechanisms or mechanisms of action in order to drive drug discovery efforts. She was a member of research teams that served to discover and/or develop aztreonam, piperacillin-tazobactam, levofloxacin, doripenem and ceftobiprole.

Dr. Bush has published over 200 peer-reviewed papers, 19 book chapters and has presented more than 225 posters or talks at international scientific meetings, many of them dealing with beta-lactamase research. She served as the Chair of Division A for ASM, was a member of the ICAAC Program Committee and is a Fellow of the American Academy of Microbiology.

Dr. Bush is currently a Professor of Practice in the Biotechnology Program at Indiana University, where she teaches a graduate level research ethics course and a course in drug development/regulatory affairs. She also leads a research group that studies new antibacterial agents and novel resistance mechanisms in Indiana Health Care Centers.

Carolyn Deal, PhD

Carolyn Deal, PhD

Dr. Deal trained as a microbiologist. She is currently at the National Institutes of Health (NIH) in Bethesda, MD. Dr. Deal is the Branch Chief of the Sexually Transmitted Diseases (STD) Branch, Division of Microbiology and Infectious Diseases, National Institute of Allergy and Infectious Diseases (NIAID). The STD Branch is responsible for the NIAID extramural program focused on sexual and reproductive tract infections and syndromes, infections which disproportionally affect adolescents, women, and infants. The program is responsible for basic research through product development and clinical trials to better understand the mechanisms of microbial pathogenesis and to develop improved diagnostics, therapeutics, and prevention strategies to control and prevent STIs.

Her education started at Purdue with a BS in Biology. She received her Ph.D. in Microbiology at the University of Illinois, Champaign-Urbana. This was followed by a postdoctoral fellowship at Scripps Clinic in La Jolla, CA. Prior to joining NIAID, Dr. Deal was as a Research Microbiologist at the Walter Reed Army Institute of Research in Washington, DC, with a laboratory focused on bacterial pathogenesis, as well as running the core facility for protein sequencing and peptide synthesis. She subsequently was at the US Food and Drug Administration as the Deputy Director for the Division of Bacterial and Allergenic Products, Office of Vaccines Research and Review, Center for Biologics Evaluation and Research. This was an opportunity to expand her interests in product development and regulation prior to the move to her current position at NIAID.

Tricia Humphreys, PhD

Tricia Humphreys, PhD

Dr. Humphreys received her B.A. in Biology at Thomas More College, a small, liberal arts college. She went on to obtain her Ph.D. in Microbiology at Miami University and completed a post-doctoral fellowship in Infectious Diseases at Indiana University School of Medicine. After her post-doc, she returned to her roots to teach at a small, liberal arts college. She is currently an Associate Professor of Biology at Allegheny College, where she is also associated with the Biochemistry and the Global Health Studies programs. Her research focuses on the biology of Haemophilus ducreyi. Her personal research interests lie in understanding the relationships between the two classes of H. ducreyi strains. Her lab is run entirely by undergraduate students who often focus on other aspects of H. ducreyi's pathogenesis.

Dr. Humphreys teaches Investigative Approaches in Biology, Microbiology, Immunology, Junior Seminar and Senior Seminar. She has mentored over 40 students in their Senior Research projects, and over 20 students through Independent Research projects, and she routinely hosts summer research students. Her students have presented at undergraduate research conferences, global health conferences, MMPC and the ASM General Meeting. Dr. Humphreys has mentored an ASM Undergraduate Research Fellow. She has co-authored publications with 9 undergraduates.

Opening Speakers

Nancy Freitag, PhD

Nancy Freitag, PhD

University of Illinois, Chicago

No pain, no gain: how the anesthetic propofol increases susceptibility to microbial infection

The Freitag lab examines the multiple ways in which pathogenic intruders gain access to host tissues and establish infections. Much of our work focuses on the environmental bacterium Listeria monocytogenes and how this organism transitions from life in the soil to life within mammalian cells. Research interests include basic mechanisms of virulence factor secretion as well as defining the factors that determine replication niches within an infected host. More recently, the Freitag lab has begun investigating how brief exposure to common anesthetic agents, such as propofol, result in dramatic increases in host susceptibility to microbial infection. Understanding the ways in which pathogens gain access to host cells and tissues will aid in the development of new strategies to limit infectious disease.

Michael Federle, PhD

Michael Federle, PhD

University of Illinois, Chicago

Code Breaking and Signal Jamming as Approaches to Disrupt Pathogenic Behavior

The Federle Lab's ongoing research interests are in cell-cell communication among bacteria, also known as quorum sensing. We have helped to identify a new class of quorum-sensing pathways that utilize secreted peptide pheromones and receptor proteins of the Rgg family. Our work focuses on characterization of these pathways and the identification of behaviors controlled by them, particularly those involved in host-pathogen interactions. We are working to develop novel therapeutics aimed at interfering with bacterial communication as a method to treat disease, disrupt bacterial biofilms, and promote health.

Other Invited Faculty Speakers

Evan Snitkin, PhD

Evan Snitkin, PhD

University of Michigan

Applications of Whole Genome Sequencing to Track the Spread of Infections in Hospitals

Dr. Snitkin is an Assistant Professor in the Department of Microbiology & Immunology and the Division of Infectious Diseases at University of Michigan Medical School. His lab is interested in the application of innovative computational and experimental approaches to study the epidemiology, evolution and physiology of multi-drug resistant (MDR) bacteria that cause healthcare-associated infections (HAI). HAIs affect 5% of hospitalized patients, result in 99,000 deaths and cost $30 billion each year in the United States alone. The diminishing efficacy of available drugs has put even more onus on infection prevention. To help meet this challenge, pat of Dr. Snitkin’s laboratory works in the emerging field of genomic hospital epidemiology. The goal of this research is to take advantage of the molecular resolution provided by whole genome sequencing (WGS), to link together bacterial isolates from different patients, and in turn understand how infections spread. Through the integration of genomic and epidemiological analyses, he hopes to elucidate both patient factors and treatments associated with the spread of infection, and thereby facilitate the implementation of evidence-based infection control measures. In addition to allowing insight into the epidemiology of hospital pathogens, WGS can provide fundamental insights into bacterial evolution. In particular, by sequencing bacteria isolated from patients, one can begin to decipher the molecular mechanisms underlying bacterial adaptations to the pressures imposed by antibiotic treatment, the host immune response and the other stresses encountered during the pathogen lifecycle. A better understanding of bacterial evolution in the context of the healthcare system will be essential for designing more effective treatments and diagnostics.

Ryan Hunter, PhD

Ryan Hunter, PhD

University of Minnesota

Airway Infections: Where good bugs go wild

Dr. Hunter is an Assistant Professor of Microbiology at the University of Minnesota. Research in the Hunter lab is broadly focused on the in vivo ecology and metabolic strategies of respiratory pathogens. Using approaches developed by traditional microbial ecologists, we strive to define the environmental chemistry of the airways, how microbes co-evolve, and how to manipulate this niche to slow disease development. Using a combination of geochemistry, single cell imaging and ecological tools, efforts are focused on two main areas of emphasis:

Carbon acquisition: The primary sources of energy for bacterial growth in the respiratory tract are poorly characterized. Our lab is defining the microbe-microbe and host-microbe interactions that sustain the bioavailable carbon budget in the infected respiratory tract, and the bacterial metabolic strategies used to obtain these resources.

Ecological dynamics of chronic sinusitis: Bacterial sinusitis affects more than 15% of the population, though the microbiology of this disease remains poorly understood. Recent 16S sequencing efforts have implicated a number of suspected pathogens, but bacterial metabolic strategies and their specific contributions to upper airway disease are not yet known. We utilize a combination of single cell imaging, proteomics, and geochemical measurements (pH, O2, nutrient sources) to characterize the ecological dynamics of chronic sinus infections.

Jacob Yount, PhD

Jacob Yount, PhD

Ohio State University

Identification of a New Cellular Target for Broadly Inhibiting Influenza Virus Infections

The Yount laboratory aims to identify and characterize post-translational modifications on innate immune system proteins, with the goal of exploiting these enzymatic modifications to control immune functions. Using chemical tools, mass spectrometry, and biochemical techniques, we have identified lipid modifications that control the activity of Toll-like receptors and the interferon-induced transmembrane protein (IFITM) family of antiviral proteins. Our ongoing studies of IFITM3 have also uncovered its regulation by additional post-translational modifications including phosphorylation and ubiquitination. This work has revealed mechanisms that govern IFITM3 cellular trafficking and turnover, and provides insight into the deleterious effects of an IFITM3 polymorphism present in the human population that increases susceptibility to severe influenza virus infections. Our most recent efforts have identified the primary E3 ubiquitin ligase responsible for promoting IFITM3 degradation. Targeting this enzyme leads to increased IFITM3 levels in cells and provides broad cellular resistance to multiple influenza virus strains. We are continuing to explore how ubiquitination and other post-translational modifications can be manipulated for prevention or treatment of infections.

Seema Mattoo, PhD

Seema Mattoo, PhD

Purdue University

From Bacterial Pathogenesis to ER Homeostasis: Fic Proteins in Cellular Signaling

Dr. Mattoo is an Assistant Professor in the Department of Biological Sciences at Purdue University. The Mattoo laboratory investigates the functional repertoire of Fic (filamentation induced by cAMP) proteins in regulating prokaryotic and eukaryotic signal transduction pathways. Post-translational modifications mediated by Fic proteins regulate critical cellular processes likes bacterial pathogenesis, cell division, drug tolerance, stress survival, and cellular trafficking. Dr. Mattoo previously discovered that the Histophilus somni virulence factor IbpA catalyzes the addition of AMP (adenosine monophosphate) to Rho GTPases to inhibit their activity. This adenylylation (also called AMPylation) event enables the bacterium to evade host defenses. Most recently, the Mattoo lab has discovered a hitherto unknown role for the sole human Fic protein, HYPE/FicD, in regulating ER homeostasis and the mammalian unfolded protein response by adenylylating the ER chaperone, BiP.

Robert Abramovitch, PhD

Robert Abramovitch, PhD

Michigan State University

Mechanisms of Mycobacterium tuberculosis pH-driven pathogenesis

Dr. Abramovitch is an assistant professor in the Department of Microbiology and Molecular Genetics at Michigan State University. The mission of his research program is to make basic and applied research discoveries that jumpstart the development of new drugs to treat tuberculosis. Towards this goal, his lab is studying how Mycobacterium tuberculosis (Mtb) senses and adapts to environmental cues encountered by the bacterium during the course of disease. His team is focused on the role of two-component regulatory systems in pH- and hypoxia-driven adaptation and determining how these regulatory networks enable the bacterium to survive in macrophages and establish persistent infections. Additionally, his lab has established a high throughput screening drug discovery platform that enables the identification of anti-virulence compounds that interfere with Mtb environmental adaptation pathways and pathogenesis.

Irene Newton, PhD

Irene Newton, PhD

Indiana University, Bloomington

Mi casa es su casa: how an intracellular symbiont maintains a persistent infection

Dr. Irene Newton graduated from Harvard University in 2008, earning a doctorate focused on functional genomics of intracellular bacterial symbionts under Dr. Colleen Cavanaugh. She was funded on an NSF postdoctoral fellowship to work on another intracellular bacterium, Wolbachia pipientis, in the laboratory of Dr. Ralph Isberg at Tufts University. She started a position at Indiana University in Fall of 2011 where her laboratory investigates host-microbe interactions in the context of persistent infections using insects as model hosts. Since establishing the Drosophila-Wolbachia study system at IU, the Newton laboratory has been able to leverage the extraordinary tools in the fly to study Wolbachia, a recalcitrant, obligately intracellular bacterium. Her recent discovery that the regulation of actin affects the maintenance and transmission of this symbiont has led to the development of a forward genetic system in Wolbachia. The laboratory is currently using both experimental evolution and classic Drosophila genetics to manipulate the symbiosis and understand the mechanisms of host-symbiont interaction.

Gustavo Arrizabalaga, PhD

Gustavo Arrizabalaga, PhD

Indiana University School of Medicine

Bursting out: role of a Calcium Dependent Protein Kinase in host cell egress by the opportunistic pathogen Toxoplasma gondii

Dr. Gustavo Arrizabalaga is an Associate Professor at Indiana University School of Medicine in the Departments of Pharmacology and Toxicology and Microbiology and Immunology. He received a B.S. in Biology and Chemistry from Haverford College in Pennsylvania and a Ph.D. in Biology from M.I.T. He performed a post-doctoral fellowship in molecular parasitology at Stanford University in the laboratory of Dr. John Boothroyd. For nearly eight years he was faculty member at the University of Idaho, where he received numerous teaching and research awards. He joined the faculty at Indiana University in May of 2012. Dr. Arrizabalaga’s research group investigates various aspect of the cell and molecular biology of the obligate intracellular parasite Toxoplasma gondii. He has focused most of his work on identifying and characterizing the signaling events and proteins that regulate the process by which the parasite exits its host cell. His laboratory is currently funded by the NIH and the American Heart Association

Jennifer Edwards, PhD

Jennifer Edwards, PhD

Nationwide Children's Hospital

TBD

Dr. Edwards’s uses primary human epithelial cell models to elucidate the pathogenic mechanisms underlying mucosal bacterial infections. Her research interests are focused on infections caused by the Neisseriaceae family, their impact on women's and neonatal health, and the mechanisms contributing to asymptomatic disease and to infectious disease disparity. She is also investigating novel therapeutic approaches to treat multi-drug resistant N. gonorrhoeae and is a member of the Gonococcal Vaccine Consortium, a panel of international experts in gonococcal pathogenesis with the mission to expedite gonococal vaccine development. Collectively, Dr. Edwards’s work has had a substantive impact on our understanding of neisserial pathogen-host interactions. She holds several patents on the treatment and prevention of diseases caused by N. gonorrhoeae and N. meningitidis and her published works have been frequently highlighted or featured by editors. She trained with Dr. Mike Apicella at the University of Iowa where she received numerous awards for her research, including the "Dean's Distinguished Dissertation Award". Dr. Edwards is an Associate Professor in the Department of Pediatrics at The Research Institute at Nationwide Children's Hospital and The Ohio State University; she has a courtesy appointment in the Department of Microbial Infection and Immunity.

Jyl Matson, PhD

Jyl Matson, PhD

University of Toledo

TBD

Jyl Matson is an Assistant Professor in the Department of Medical Microbiology and Immunology at the University of Toledo College of Medicine and Life Sciences. Her laboratory is interested in the mechanisms by which bacteria sense and respond to their extracellular environment. Vibrio cholerae is the bacterium that causes epidemic cholera, a disease that continues to spread in areas of the world where people lack access to clean drinking water. Due to increasing antibiotic resistance among V. cholerae strains, there is a need to develop additional therapeutic agents for cholera treatment. Current projects in the Matson lab include identification and characterization of small molecule inhibitors of a V. cholerae stress response pathway that may be developed into cholera therapeutics. Additional studies aim to characterize transcriptional responses of V. cholerae to various stresses to determine pathways associated with bacterial fitness and pathogenesis.

Blaise Boles, PhD

Blaise Boles, PhD

University of Iowa

Microbial Functional Amyloids – pushing Staphylococcus aureus to new places.

My primary research interests lie in defining molecular mechanisms utilized by human commensal bacteria to colonize, persist on, and disperse from biologically relevant surfaces. Much of the current work in my lab centers around elucidating the role of functional amyloids produced by Staphylococcus aureus during surface colonization and dispersal. Amyloids are remarkably stable protein polymers that form β-sheet rich fibers and the amyloid fold is unique in that it is adopted by a range of proteins with varying primary sequences. Until recently amyloids were considered solely the result of protein misfolding and associated with many human neurodegenerative diseases. However, recent research has revealed many microbes have capitalized on the amyloid fold and utilize amyloids for such functions as reinforcing biofilms, storing toxins, and promoting motility. How microbes manipulate amyloids, by augmenting their advantageous properties and by reducing their undesirable properties, is the subject of current inquiry.

Nick Cianciotto, PhD

Nick Cianciotto, PhD

Northwestern University

The multi-faceted nature and importance of Legionella pneumophila secretion: Beyond Dot/Icm type IV secretion

Dr. Cianciotto is a Professor in the Department of Microbiology-Immunology at Northwestern University Medical School in Chicago. His laboratory studies the molecular pathogenesis of Legionella pneumophila and Stenotrophomonas maltophilia, two important agents of pneumonia. Among other things, the lab studies the role of type II protein secretion in virulence, siderophores, secreted pigments, and other aspects of iron acquisition, and non-canonical roles for CRISPR-Cas.

Francis Alonzo, PhD

Francis Alonzo, PhD

Loyola University

Staphylococcus aureus suppression of immune responses via metabolic cofactors

Dr. Alonzo is an Assistant Professor in the Department of Microbiology and Immunology at Loyola University - Chicago. His laboratory is interested in studying the physiology and pathogenic actions of Staphylococcus aureus during host infection. Particular areas of interest include deciphering the mechanisms of action of secreted virulence factors and defining bacterial interactions with immune cells at the host-pathogen interface. Currently, he is exploring the functions of a number of novel immunosuppressive factors secreted by S. aureus that dampen macrophage pro-inflammatory responses. This suppression of macrophage activity significantly enhances bacterial survival in vivo. His research uses a multi-faceted approach, incorporating elements of bacterial genetics, biochemistry, immunology, cell biology, as well as murine infection models to define the molecular mechanisms by which these immunomodulatory factors suppress macrophage functions in vitro and in vivo.

Patrick Degnan, PhD

Patrick Degnan, PhD

University of Illinois, Urbana

Gut Reactions: Evolution and Dynamics of Human Intestinal Microbes

Bacterial symbioses are ubiquitous in nature, playing integral roles in the health, ecology, evolution, and development of diverse eukaryotic hosts. Furthermore gene content in Bacteria is indicative of metabolic capacity, which in turn reflects bacterial lifestyles. The Degnan lab is interested in leveraging computational, functional and evolutionary genomic approaches to studying the effect of genetic, regulatory, and genomic evolution in human gut symbionts and their ability to compete in the gut. Currently, the Degnan lab’s research is focusing on questions that will (i) identify small molecules that impact microbial fitness and colonization of the mammalian gut, (ii) uncover the importance and interactions of regulatory RNAs in gut microbes, and (iii) identify and track novel mobile genetic elements and the microbes they impact. This work is centered on examining these mechanisms and dynamics in diverse members of the phylum Bacteroidetes, which can constitute upwards of 60% of the bacterial communities in the large intestines of some individuals and includes the model gram negative, anaerobe Bacteroides thetaiotaomicron.

Tim Wencewicz, PhD

Tim Wencewicz, PhD

Washington University in St. Louis

New Antibiotics from Nature’s Chemical Inventory

Tim Wencewicz is an assistant professor in the Department of Chemistry at Washington University in St. Louis. His lab studies the molecular mechanisms of antibiotic action, resistance, biosynthesis, and membrane permeation. Areas of particular interest include the study of antimetabolites from Pseudomonads and Streptomyces in soil. Currently, we are exploring a new class of mechanism-based glutamine synthetase (GS) inhibitors based on the phytoxin tabtoxinine-beta-lactam (TBL) produced by plant pathogenic strains of Pseudomonas syringae. We have characterized the kinetics and molecular mechanism of GS inhibition by TBL along with several potential antibiotic resistance mechanisms. Our studies indicate that GS inhibition is a promising therapeutic strategy for treating urinary tract infections caused by multi-drug resistant Gram-negative pathogens.