Grant: Foundation Grant

Antibiotic Resistance; Antibiotics; Bacterial Genetics; Bacterial Pathogenesis; Cholera; Microbial Competition; Microbiome; T6ss; Type Vi Secretion System; Vibrio Cholerae

<html> <body> <p> <b>Program Focus:</b> Drug-resistant variants of disease-causing bacteria are emerging in alarming numbers. Current antibiotics target essential bacterial functions and apply selective pressure that leads to antibiotic resistance (<i>1</i>). Novel therapies must disarm pathogens instead of killing them, to reduce selection pressure and resistance. <b>With that goal in mind, my research focuses on interactions of pathogenic bacteria with their host, and the disclosure of novel targets for therapeutic strategies that discourage resistance.</b> <br> <br> <b>Overarching Direction and Major Issues:</b> The CDC estimates that every year more than 2 million people contract antibiotic-resistant infections in the US alone and 23,000 die of previously treatable infections, a number that continues to increase (<i>1</i>). Another study prepared for the UK Prime Minister predicts that 300 million people will die of antibiotic-resistant infections by 2050 unless alternative therapies are developed (<i>2</i>). These disturbing statistics indicate a return to the pre-antibiotic era. To discover much-needed novel antimicrobial therapies, I pioneered the use of the genetically tractable amoeba <i>Dictyostelium discoideum</i> <b>(<i>3</i>)</b>. This led to my discovery of a critical protein secretion pathway, the type VI secretion system (T6SS), in <i>Vibrio cholerae</i> <b>(<i>4</i>)</b> &mdash; the causative agent of the diarrheal disease cholera (<i>5</i>). My discovery launched a new field of microbiological research because T6SS genes were subsequently identified in 25% of Proteobacteria <b>(<i>6</i>-<i>7</i>)</b>.<br> <br> The T6SS assembles as a molecular syringe to inject T6SS effectors into target cells on contact <b>(<i>8</i>)</b>. As bacteria compete for space and nutrients, species like <i>V. cholerae</i> use T6SS effectors to kill and outcompete other bacteria, unless targeted bacteria produce immunity proteins that bind and deactivate effectors (<b><i>9</i></b><i>, 10</i>). We recently discovered that different <i>V. cholerae</i> strains utilize distinct effectors that degrade structural components (peptidoglycan layer or inner membrane) of prey bacteria <b>(<i>11, 12</i>)</b>. Strains with different effector/immunity sets compete with each other, while strains with the same set are compatible and co-exist when they make contact <b>(<i>13</i>)</b>. Compatible bacteria may exchange genetic information (including virulence traits) on contact to evolve through kin selection (<b><i>13</i></b><i>, 14</i>).<br> <br> <b>Advancing Knowledge and Implications for Healthcare:</b> We aim to obtain a molecular understanding of competitive fitness in pathogenic bacteria and its impact on how virulence evolution leads to disease. We hypothesize that virulence can be inhibited without generating resistance, by targeting the T6SS. Our rationale is based on evidence that immunity genes are not essential for growth and viability until bacteria come in close contact with each other. <b>We will focus on the contribution of the T6SS to pathogenesis, and identify lead compounds for novel antimicrobials.</b> <br> <br> <b>Core Expertise:</b> My laboratory has expertise in bacterial genetics, biochemistry, cell biology and genomics. Recently established collaborations with crystallographer Alexei Savchenko (UToronto) and biophysicist Jack Tuszynski (UAlberta) bring structural biology to our approach. A longer-standing collaboration with Dr. Daniele Provenzano (UTexas) <b>(<i>13, 15-17</i>)</b> has helped us explore T6SS diversity in <i>V. cholerae</i>.<br> <br> <b>Mentoring:</b> My trainees blend microbiology and cell biology skills to study how pathogens cause disease. Their training prepares them for careers in bioscience, medicine and biotechnology.</p> </body> </html>