Investigator:
  Michael Aldape, PhD
  

Scientific Discipline: Anaerobic Microbiology

COBRE Project:  Exotoxin synergy in driving leukemoid reactions during C. difficile and C. sordellii infections

Background:  S. aureus infections remain clinically problematic due to continually evolving antimicrobial resistance.  Pathogenesis is attributed to production of potent extracellular toxins, and prolongs 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) antibiotic-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 to S. aureus to subinhibitory doses of nafcillin throughout different phases of bacterial growth.  2) To determine the role of S. aureus divisome proteins in nafcillin-induced toxin expression.  3) To determine the effect 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.

Mentors:  Stuart Johnson, M.D. and Amy Bryant, PhD

About Dr. Aldape:  Dr. Aldape is a nationally recognized early-stage investigator in clostridial pathogenesis.  He graduated from the joint VA/BSU/UI PhD program in Microbiology in 2006, and completed a 3-year VA Career Development Award that investigated the role of exotoxins the extreme leukemoid reaction (LR) characteristic of severe C. sordellii infection.  His current COBRE project is an extension of this work.  Dr. Aldape received Pfizer’s prestigious, nationally-competitive ASPIRE award for young investigators, and currently has two industry-supported grants to study the effects of novel antibiotics on exotoxin production and sporulation by hyper-virulent C. difficile.  He is also seeking NIH R21 support for design of small molecule inhibitors of the large family of MF4 proteases of which novel C. sordellii metalloproteinase – to be studied here – in one.  As Assistant Professor of Biology at Northwest Nazarene University (an INBRE affiliate), Dr. Aldape provides annual summer research opportunities for NNU undergraduates, and of 5 such INBRE-supported students he has mentored, 3 are currently in medical school, and 2 are in post-graduate research programs.  Dr. Aldape is a voting member of the VA’s R&D Committee and chairs the VA’s IACUC.

IVREF