Mark S. Smeltzer ('14)

(Speaker Term: 7/1/12 - 6/30/14)
Department of Microbiology and Immunology
University of Arkansas for Medical Sciences
4301 W. Markham, Mail Slot 511       
Little Rock, AR  72205
Phone: 501-686-7958
Fax: 501-686-5359   

Staphylococcus aureus: Would the Real Pathogen Please Stand Up?
All strains of a bacterial species are not created equal, and it is imperative that this diversity be taken into account when developing improved therapeutic approaches.  We address this by focusing on strains of S. aureus precisely because they are different from each other; in effect, we look for the outliers based on the belief that the inability to find them increases the likelihood that we will uncover central themes that can be used to therapeutic advantage.

Bad to the Bone: Staphylococcus aureus as a Musculoskeletal Pathogen
S. aureus is the leading cause of all forms of musculoskeletal infection, and this cannot be explained by exposure alone.  Thus, S. aureus must have specific attributes that define it as a musculoskeletal pathogen, and we are attempting to identify these in order to exploit them to diagnostic and therapeutic advantage.

Nanotechnology: A Tiny Solution to the Big Problem of Staphylococcus aureus Biofilm Associated Infections?
The limitations of conventional antimicrobial therapy have become readily apparent in recent years, and this is perhaps most evident in biofilm-associated infections.  Nanotechnology is the science of very small particles, which means they have comparatively large surface areas, and this lends them properties that can be exploited for the targeted physical destruction of bacterial cells irrespective of their antibiotic-resistance status. 

Extracellular Proteases: Forcing Staphylococcus aureus to Expose Itself
Sometimes it’s not what you do but what you don’t do.  In the case of S. aureus, not making extracellular proteases is a key component of multiple forms of infection.  Thus, we propose to make S. aureus do what it doesn’t want to do, thereby exposing itself to both host defenses and antimicrobial agents. 


I have focused my research efforts on the pathogenesis of Staphylococcus aureus infection since 1990 when I joined the laboratory of Dr. John J. Iandolo at Kansas State University as a post-doctoral research associate.  I left Kansas State in 1993 to join the faculty at the University of Arkansas for Medical Sciences (UAMS) based largely on the opportunity to work with the chair of Orthopaedic Surgery at UAMS, Dr. Carl L. Nelson.  This afforded me the chance to focus my basic science research on the clinically-relevant problem of musculoskeletal infection.  This work led to a specific interest in biofilm as an important complicating factor in the successful treatment of these infections. 


We have taken a global approach to our work that includes efforts to improve methods for the early diagnosis of musculoskeletal infection, optimizing methods for local antibiotic delivery in the treatment of infection, and defining the mechanistic basis for S. aureus biofilm formation.  With respect to the latter, our focus has been on defining differences between strains of S. aureus as they relate to the capacity to form a biofilm with a specific emphasis on defining not only how specific genes impact biofilm formation per se but also the intrinsic resistance that is characteristic of biofilm-associated infection.  This work led us to place a primary emphasis on the staphylococcal accessory regulator (sarA) as a therapeutic target, and much of our current work is now directed toward developing alternative therapeutic strategies that take advantage of the important role of sarA in biofilm formation. 


We are pursuing three avenues in that regard. The first is the direct identification of small molecule inhibitors of sarA-mediated biofilm formation; the logic in this case being that such inhibitors could be used as adjunct therapy to conventional antimicrobial therapy to overcome the intrinsic resistance of biofilm-associated infections.  The second is defining the mechanistic basis for the biofilm-deficient phenotype of S. aureus sarA mutants. These studies have led us to conclude that a primary factor contributing to the biofilm-deficient phenotype of S. aureus sarA mutants is their increased production of extracellular proteases and the impact of these proteases on specific surface-associated proteins.  Based on this work we have initiated a third avenue of research focused on developing an alternative nanotherapeutic strategy targeting these surface proteins as a means of effectively killing biofilm-associated staphylococci irrespective of their metabolic status.  I believe that my laboratory is uniquely placed to pursue these studies based on our expertise in staphylococcal biology and pathogenesis and the expertise of our UAMS collaborators in all other relevant areas including pediatric infectious disease, nuclear medicine, orthopaedic surgery, and biophysics.

Primary Division:       B (Microbial Pathogens)

Secondary Division:   H (Genetics & Molecular Biology)