Investigator:  Devin Bolz, PhD

Scientific Discipline: Cell Signaling Transcriptome

COBRE Project:  Impact of antibiotics on growth cycle and toxin production in S. aureus

BackgroundS. aureus infections remain clinically problematic due to continually evolving antimicrobial resistance.  Pathogenesis is attributed to production of potent extracellular toxins, and recent evidence from our laboratory has shown that beta-lactam antibiotics, such as nafcillin, increase and prolong toxin production in methicillin-sensitive and methicillin-resistant S. aureus (MRSA).  The current study investigates detailed molecular mechanisms by which cell-wall active antibiotics alter the S. aureus divisional apparatus (divisome) and stimulate toxin production.

Hypothesis:  We hypothesize that a) cell-wall active antibiotics induce toxin expression via a unique and uncharacterized stress-response pathway; b) antiobiotic-induced toxin expression is orchestrated via divisome elements PBP1 and/or PknB; and c) antibiotic-induced toxin expression has a significant impact S. aureus pathogenesis.

Specific Aims:  1) To determine the transcriptional response of S. aureus to subinhibitory doses of nafcillin throughout different phases of bacterial growth.  2) To determine the role of S. aureus to divisome proteins in nafcillin-induced toxin expression.  3) To determine the effects of subinhibitory levels of nafcillin on S. aureus pathogenicity. 

Impact on Human Health:  Understanding molecular mechanisms that drive S. aureus toxin production in response to cell-wall active antibiotics will identify novel targets for disease intervention.

Mentor:  Rodney Tweten, PhD

About Dr. Bolz:  Dr. Bolz completed his PhD in Immunology in 2006 at the University of Utah and his post-doctoral research at Duke University in 2010.  His work focused on pathogenic mechanisms of vector-borne bacterial pathogens including Borrelia burgdorferi and Yersinia pestis.  He described fundamental roles for the Toll-like receptor adapter protein, MyD88, in controlling bacterial burden and inflammation in response to Borrelia spp, and innate inflammatory signaling in Lyme arthritis.  Additionally, using microarray gene expression analysis in C. elegans, he demonstrated that a highly conserved p38 MAPK pathway modulates transcriptional activity of several innate immune defenses toward Y. pestis.  Dr. Bolz joined the Infectious Diseases research team in 2011 where he established the signaling mechanisms of streptolysin O-induced cardiomyocyte dysfunction in vitro.  He has an independent industry-supported grant to study the effects of a novel antibiotic on exotoxin gene expression and protein production in S. aureus.   His COBRE project is an extension of this work.  Dr. Bolz is an affiliate faculty member in the Biomolecular Research Center at BSU (an INBRE-supported facility), a mentor for INBRE-supported summer research fellows, a voting member of the VA’s Biosafety and R&D Committees, and is a resource for investigators utilizing genome-wide transcriptional analysis of their research.

IVREF