Philip N. Rather, PhD

Professor

Microbiology and Immunology

ARTDTP Research Discipline

The Rather lab is interested in the mechanisms that regulate biofilm formation by Acinetobacter baumannii and how this impacts antibiotic resistance. The first mechanism involves quorum sensing, mediated by the signal 3-OH-C12- HSL. This signal is produced by the AbaI autoinducer synthase and an abaI mutant exhibits a 40% reduction in biofilm formation. To identify quorum sensing regulated genes that are important for biofilm formation, RNA- Seq is being used, followed by inactivation of candidate genes predicted to have a role in biofilm formation. The second pathway regulating biofilm formation occurs in cyochromeo oxidase (cyo) mutants and under microaerophilic (low oxygen) growth conditions. Both conditions result is a drastic increase in biofilm formation by what seems to be a common mechanism. It is hypothesized that cyo mutations or microaerophilic growth alters one or more components of the electron transport chain, which are then coupled to a regulatory pathway controlling biofilm formation. RNA-Seq and transposon mutagenesis are being used to identify components of this pathway. Ultimately, the group will develop small molecule or antibody-based inhibitors that directly inhibit biofilm formation and virulence by targeting the following processes: (i) quorum sensing via 3-OH-C12-HSL signaling, (ii) the oxygen sensing pathway that triggers biofilm formation, and (iii) specific gene products critical to biofilm formation and or motility. Recently, they have made significant progress in the identification of small molecule inhibitors of quorum sensing. One class of inhibitors is derived from N-acyl homoserine lactones and has IC50 values in the low micromolar range. A second inhibitor that was recently identified is the aminoglycoside antibiotic streptomycin, which acts at subinhibitory concentrations to block production of 3- OHC12-HSL. The mechanism of this inhibitory effect is currently under investigation.

ARTDTP Faculty Collaborators

Joanna B. Goldberg, PhD

Timothy D. Read, PhD

William M. Shafer, PhD

David S. Weiss, PhD