Bioinformatics; Genomics and proteomics; Infectious Disease; Microbial Pathogenesis; Molecular and Cellular Biology; Protein Function and Structure; Proteins and metalloenzymes; Structural Biology; Virology; X-ray Crystallography
The overarching goal of the Umland Lab is to use structural biology combined with biochemical, molecular biology, and genetics to explore important elements of infectious disease. The objective is to both extend the fundamental understanding of how microbial pathogens interact with their respective hosts and to identify new antimicrobial targets and new antimicrobial therapeutics.
Two major projects on this theme are on going within the lab. In the first, unrecognized and underexploited potential antimicrobial targets within multi-, extreme, and pan-drug resistant gram-negative bacilli (GNB) are being identified and then characterized using the phenotype of in vivo essentiality. That is, our interest is in genes and their corresponding gene products that are essential for bacterial growth and survival during infection of a host (i.e., in vivo) rather than only essential under ideal laboratory growth conditions (e.g., rich laboratory media, absence of immune responses, etc.). The class of genes that are in vivo essential but not in vitro essential has largely been neglected as antimicrobial targets, and so represents a rich set for expanding target space in the urgent race to develop new antimicrobials.
The second project is focused upon identifying and characterizing virus protein - host protein interactions. Viruses encode a highly limited set of functionality, and therefore rely on subverting cellular machinery. This high jacking of cellular functions for the benefit of the virus often involved virus-host protein-protein interactions (PPIs). Study of these virus-host PPIs reveals both the mechanisms by which viruses co-opt cellular functions and potential new antiviral targets recalcitrant to the development of drug resistance. An additional rationale for studying virus-host PPIs is to understand virus evolution with respect to PPI involvement in virulence, pathogenesis, and host tropism.
In conjunction with both of these projects, the Umland Lab is using structurally enabled fragment-based lead discovery (FBLD) methods to identify small molecules with potential to be developed into antimicrobial therapeutics.