Department of Microbiology & Immunology and Department of Orthopaedics
Research Interest: Molecular Pathogenesis of Staphylococcus aureus infections
Ph.D.: Kansas State University
Postdoctoral: Kansas State University
Phone: 501-686-7958 or 501-686-5254
After receiving his Ph.D. from Kansas State University, Dr. Smeltzer completed post-doctoral training in the laboratory of Dr. John J. Iandolo. It was in Dr. Iandolo’s lab that he was first introduced to Staphylococcus aureus as a bacterial pathogen. His goal during that time wasn’t so much to learn about S. aureus but rather to learn the experimental tools of molecular biology, which he then hoped to apply to an as yet to be determined biomedical problem. Dr. Smeltzer was recruited to UAMS in 1993 by the former chair of the Department of Orthopaedic Surgery, Dr. Carl L. Nelson. His recruitment to UAMS was based on the observation that S. aureus was and continues to be the leading cause of infections involving bone and indwelling orthopaedic devices. These infections are remarkably difficult to treat even when the offending bacterial strain is susceptible to the preferred antibiotics. This most often necessitates surgical intervention to remove infected tissues and/or indwelling devices, and even then the recurrence rate of infection is unacceptably high. Thus, a primary goal of the Smeltzer laboratory has been to understand the pathophysiology of Staphylococcus aureus as an orthopaedic pathogen to a degree than can be exploited to prophylactic and therapeutic advantage.
This work has led to a focus on the staphylococcal accessory regulator (sarA), mutation of which limits the ability of S. aureus to form a biofilm to a degree that can be correlated with increased antibiotic susceptibility. It also limits overall virulence in the context of sepsis, osteomyelitis, and implant-associated infection. Based on this, current research funded by the Peer-Reviewed Orthopaedic Research Program within the Congressionally-Directed Medical Research Program is aimed at identifying small molecule inhibitors of sarA and developing more effective methods for the delivery of these inhibitors, together with conventional antibiotics, directly to the site of infection. In work funded by the National Institute of Allergy and Infectious Disease (NIAID), the Smeltzer lab is also investigating the mechanistic basis by which sarA impacts all of these clinically-relevant phenotypes. This has led to the hypothesis that the inability of sarA mutants to repress the production of extracellular proteases plays a critical role owing to the fact that it limits the accumulation of S. aureus virulence factors that contribute to these infections. This impact of these proteases is currently being exploited to comprehensively identify these virulence factors using a proteomics approach.
In collaboration with the laboratory of Dr. Jingyi Chen at the University of Arkansas-Fayetteville, the Smeltzer laboratory is exploring the use of a novel nanotherapeutic approach to the treatment of S. aureus infections. This approach employs photoactivatable antibody-conjugated, antibiotic-loaded gold nanocages to achieve a lethal photothermal effect and the simultaneous release of antibiotics directly at the surface of the targeted bacterial cells. Work to date confirms that it is capable of eradicating an established S. aureus biofilm, a result that cannot be achieved using any concentration of conventional antibiotic alone. With support from the Texas Hip and Knee Foundation, and in collaboration with Dr. Alexandru Biris at the University of Arkansas at Little Rock and Dr. David Anderson at the University of Tennessee-Knoxville, the Smeltzer laboratory is also exploring the use of a nanoparticle based “scaffold” that can be used to deliver antibiotics directly to the site of infection and simultaneously promote bone regeneration across segmental bone defects following traumatic injury and/or radical surgical debridement.
Brann, K.R., Fullerton, M.S., Onyilagha, F.I., Prince, A.A., Kurten, R.C., Rom, J.S., Blevins, J.S., Smeltzer, M.S., Voth, D.E. 2019. Infection of Primary Human Alveolar Macrophages Alters Staphylococcus aureus Toxin Production and Activity. Infect Immun. 20;87(7). pii: e00167-19.
Blom, A., Cho, J., Fleischman, A., Goswami, K., Ketonis, C., Kunustor, S., Makar, G., Meeker, D.G., Morgan-Jones, R., Ortega-Peña, S., Parvizi, J., Smeltzer, M., Stambough, J.B., Urish, K., Tonelo Zilotto, G.P. General assembly, prevention, antiseptic irrigation solution: Proceedings of International Consensus on Orthopedic Infections. J Arthroplasty. Oct 19, Epub ahead of print.
Byrum, S.D., Loughran, A.J., Beenken, K.E., Orr, L.M., Mackintosh, S.G., Edmondson, R.D., Tackett, A.J., and Smeltzer, M.S. Label-free proteomic approach to characterize protease-dependent and independent effects of sarA inactivation on the Staphylococcus aureus exoproteome. ACS Journal of Proteome Research, 17:3384-3395. PMCID: PMC6209314.
Meeker, D.G., Wang, T., Harrington, W.N., Zharov, V.P., Johnson, S.A., Jenkins, S.V., Oyibo, S., Walker, C.M., Mills, W.B., Shirtliff, M.E., Beenken, K.E., Chen, J., and Smeltzer, M.S. Versatility of targeted antibiotic-loaded gold nanoconstructs for the treatment of biofilm-associated bacterial infections. International Journal of Hyperthermia, 34:209-219. PMCID: PMC6095133.
Moon, S.E., Zhang, X., Zheng, G., Meeker, D.G., Smeltzer, M.S., and Huang, E. 2017. Novel Linear Lipopeptide Paenipeptins with Potential for Eradicating Biofilms and Sensitizing Gram-Negative Bacteria to Rifampicin and Clarithromycin. Journal of Medicinal Chemistry, 60:9630-9640.
Rom, J.S., Atwood, D.N., Beenken, K.E., Meeker, D.G., Loughran, A.J., Spencer, H.J., and Smeltzer, M.S. Impact of Staphylococcus aureus regulatory mutations that modulate biofilm formation in the USA300 LAC on virulence in a murine bacteremia model. Virulence, Epub ahead of print.
Meeker, D.G., Loughran, A.J., Beenken, K.E., Spencer, H.J., Lynn, W.B., Mills, W.B., and Smeltzer, M.S. 2016. Evaluation of antibiotics effective against methicillin-resistant Staphylococcus aureus based on efficacy in the context of an established biofilm. Antimicrobial Agents and Chemotherapy, 60:5688-5694.
Loughran, A.J., Gaddy, D., Beenken, K.E., Meeker, D.G., Morello, R., Zhao, H., Byrum, S.D., Tackett, A.J., Cassat, J.E., and Smeltzer, M.S. 2016. Impact of sarA and phenol-soluble modulins in the pathogenesis of osteomyelitis in diverse clinical isolates of Staphylococcus aureus. Infection and Immunity, 84:2586-2594. PMCID: PMC4995912.
Atwood, D.N., Beenken, K.E., Loughran, A.J., Meeker, D.G., Lantz, T.L., Graham, J.W., Spencer, H.J., and Smeltzer, M.S. 2016. XerC contributes to Staphylococcus aureus biofilm-associated versus acute infections via agr-independent and agr-dependent pathways respectively. Infection and Immunity. 84:1214-1225.
Meeker, D.G., Jenkins, S.V., Miller, E.K., Beenken, K.E., Loughran, A.J., Powless, A., Muldoon, T.J., Galanzha, E.I., Zharov, V.P., Smeltzer, M.S., Chen, J. (Meeker and Jenkins, co-first authors; Smeltzer and Chen, co-corresponding authors.) 2016. Synergistic photothermal and antibiotic killing of biofilm-associated Staphylococcus aureus using targeted, antibiotic-loaded gold nanoconstructs, ACS Infectious Disease. 2:241–250.
Atwood, D.N., Beenken, K.E., Lantz, T.L., Meeker, D.G., Lynn, W.B., Mills, W.B., Spencer, H.J., and Smeltzer, M.S. 2016. Regulatory mutations impacting antibiotic susceptibility in an established Staphylococcus aureus biofilm. Antimicrobial Agents and Chemotherapy, 2016 60:1826-182.
Atwood, D.N., Loughran, A.J., Courtney, A.P., Anthony, A.C., Meeker, D.G., Spencer, H.J., Gupta, R.K., Lee, C.Y., Beenken, K.E., Smeltzer, M.S. 2015. Comparative impact of diverse regulatory loci on Staphylococcus aureus biofilm formation. MicrobiologyOpen. 4:436-451.
Loughran, A.J., Atwood, D.N., Anthony, A.C., Harik, N.S., Spencer, H.J., Beenken, K.E., and Smeltzer, M.S. 2014. Impact of individual extracellular proteases on Staphylococcus aureus biofilm formation in diverse clinical isolates and their isogenic sarA mutants. MicrobiologyOpen, 3:897-909.
Beenken, K.E., Mrak L.N., Zielinska, A.K., Atwood, D.N., Loughran, A.J., Griffin, L.M., Matthews, K.A., Anthony, A.C., Spencer, H.J., Post, G.R., Lee, C.Y., and Smeltzer, M.S. 2014. Impact of the functional status of saeRS on in vivo phenotypes of sarA mutants in Staphylococcus aureus. Molecular Microbiology, 92:1299-1312.
Cassat, J.E., Hammer, N.D., Campbell, P., Benson, M.A., Perrien, D.S., Mrak, L.N., Smeltzer, M.S., Torres, V.J., Skaar, E.P. 2013. A secreted protease tailors the Staphylococcus aureus virulence repertoire to modulate bone remodeling during osteomyelitis. Cell Host and Microbe, 13:759-772.
Zielinska, A.K., Beenken, K.E., Mrak, L.N., Spencer, H.J., Post, G.R., Skinner, R.A., Tackett, A.J., Horswill, A.R., Smeltzer, M.S. 2012. sarA-mediated repression of protease production plays a key role in the pathogenesis of Staphylococcus aureus USA300 isolates. Molecular Microbiology, 86:1183-1196.