Using a chemistry based multidisciplinary approach we explore various aspects of bacterial virulence.
My group is currently engaged in three reserach areas: inhibitors of bacterial virulence systems, chemical probes to study ADP-ribosyltransferases, and antiviral small molecules and glycoconjugate.
Inhibitors of bacterial virulence systems
Using a chemistry based multidisciplinary approach we explore various aspects of bacterial virulence. The ultimate goal is to generate knowledge that will lead to highly specific antibacterial regimens that counteract the virulence mechanisms of the pathogens and minimize the risks for development of resistance. Virulence can broadly be defined as the capacity of a microorganism to cause disease. The main focus is on the evolutionary conserved type III secretion (T3S) virulence systems that are shared by several clinically important mammalian pathogens including Yersinia spp., Salmonella spp., Shigella spp., Pseudomonas aeruginosa, enteropathogenic and enterohaemorrhagic Escherichia coli, and Chlamydia spp. During the infection the bacterium adheres to a eukaryotic cell membrane and with the T3S machinery it injects a set of toxins into the lumen of the target cell and thereby subvert host defense mechanisms. We use screening-based strategies to identify natural and synthetic T3S inhibitors and use total synthesis, statistical molecular design, structure-based design and computation of quantitative structure-activity relationships in the subsequent optimization. Compounds are evaluated in a wide variety of assays including cell-based and in vivo infection models with focus on Yersinia spp., Pseudomonas aeruginiosa, and Chlamydia spp. Currently we have identified and optimized virulence inhibitors active against a number of bacterial species and established efficacy in vitro and in vivo.
Chemical probes to study human ADP-ribosyltransferases
In biology, and specifically genetics, epigenetics is the study of heritable changes in gene expression or cellular phenotype caused by mechanisms other than changes in the underlying DNA sequence. ADP-ribosylation plays a critical role in cell differentiation, proliferation, genome integrity and cell-survival but the exact molecular mechanisms and its role in epigenetics remain elusive. The human diphtheria toxin-like ADP-ribose transferase (ARTD) family, also known as the poly (ADP-ribose) polymerase (PARP) family is composed of 17 members that all share a catalytic ADP ribose transerase domain. The most common human enzyme ARTD1/PARP1, and its closest relative ARTD2/PARP2, are the most studied proteins in the family and ARTD1 has been a target for drug discovery for more than a decade. Very little is however known on the biological function of the remaining family members. Our project aims to develop small molecules, chemical probes, to study ADP-ribosylation and its potential roles in epigenetic signaling. We have adopted a structure-based approach to develop potent chemical probes that show specificity towards individual members of the ARTD family. As a basis for this program we assembled a collection of compounds based on known ART inhibitors, and characterized their interactions with the catalytic domains across the entire family. In addition, we solved crystal structures of ART catalytic domains in complex with compounds identified as hits from this collection. Collectively these data provide insights into the structural determinants of inhibitor specificity, and has been used as starting points in a structure-guided medicinal chemistry program to generate selective and potent inhibitors of human ARTDs as well bacterial ADP-ribosylating toxins such as ExoS from P. aeruginosa.
Antiviral small molecules and glycoconjugates
Human adenoviruses are very common pathogens with more than 50 different serotypes forming six different species, A to F. Adenoviruses are associated with a wide variety of clinical symptoms in humans, such as upper respiratory illness, acute respiratory disease, gastroenteritis, hemorrhagic cystitis, and also keratoconjunctivitis. Although these infections can develop into severe diseases they are commonly self-limited in otherwise healthy individuals. The problem is however much more pronounced in immunocompromised individuals. Today there is no formally approved therapy for adenovirus infection and existing antiviral drugs give inconsistent results. To address this shortcoming we have employed strategies based on glycoconjugates and small drug-like molecules to target different steps of the adenoviral life cycle. Such molecules constitute research tools for manipulation of the viral life cycle and starting points for development of antiadenoviral therapies. This knowledge is also transferred into design and synthesis of compounds against other viruses e.g. Rift Valley fever virus and Zika virus.