Dr. Slayden’s laboratory studies a variety of emerging and medically important pathogens including multi-drug resistant M. tuberculosis and NTMs, F. tularensis, B. pseudomallei, Y. pestis and B. anthracis. This research allows for targeting of the unique metabolic activities of these bacterial populations.
Critical gaps in knowledge still remain regarding bacterial regulatory mechanisms as they relate to cell cycle progression, coordination of cell division and elongation, and compartmentalization of cell division and cell wall biosynthesis. Using a “biology first” approach allowed us to establish important links between key regulatory mechanisms involved in cell cycle progression-adaptive metabolism-TA loci resulting in asymmetric division, phenotypic differentiation, and population heterogeneity.
Streamlining drug discovery to progress and prioritize candidates and identify clinically relevant molecular targets remains a challenge. We have elucidated in vitro-in vivo relationships and information about drug efficacious mode of action, and host-pathogen interactions, specifically dynamics between the host response. In addition to improving the discovery of drugs with efficacy in animal models of infection, this research has resulted in the development of novel therapeutic interventions that involve both traditional target-based small molecular drug discovery and the development of host immune-modulatory potentiating agents.
The Slayden laboratory uses this information in a multi-disciplinary approach to drug discovery and development of preclinical lead compounds and potentiating agents with efficacy against specialized bacterial populations.
Regulation of toxin-antitoxin loci and adaptive responses
The vast majority of encoded TA loci are induced as part of various adaptive responses to host-associated environmental stress (hypoxia, carbon limitation, and pH), the activation status of infected phagocytes and the development of cell-mediated immunity to infection.
Bacterial co-infections in viral disease
It is well known that respiratory viral infections predispose patients to secondary bacterial infections, and this situation leads to increased severity and mortality. The two-hit hypothesis suggests that a viral infection, even sub-clinical increases susceptibility to bacterial co-infections, thus influencing disease progression, severity and outcomes.
Compartmentalization of Cell Division and Cell Wall Biosynthesis in M. Tuberculosis
This model proposes, when division occurs, each cell inherits an aged elongating pole from a previous round of cell division, and a newly formed pole from the recent septa. The observed differences in bacterial cell length is governed by a longer duration of elongation at the older pole compared to the newly formed pole. Thus, each round of division increases the overall population heterogeneity.
Slayden RA, Dawson CC, Cummings JE.
Pathog Dis. 2018 Jun 1;76(4). doi: 10.1093/femspd/fty039. Review.
Transient In Vivo Resistance Mechanisms of Burkholderia pseudomallei to Ceftazidime and Molecular Markers for Monitoring Treatment Response.
Jason E. Cummings, Richard A. Slayden.
PLOS Neglected Tropical Diseases. 2017. 11(1):e0005209. PMID: 28081127.
MadR1, a Mycobacterium tuberculosis cell cycle stress response protein that is a member of a widely conserved protein class of prokaryotic, eukaryotic and archeal origin.
Crew R, Ramirez MV, England K, Slayden RA.
Tuberculosis (Edinb). 2015 May;95(3):251-8. doi: 10.1016/j.tube.2015.03.005. Epub 2015 Mar 13.
Cell division inhibitors with efficacy equivalent to isoniazid in the acute murine Mycobacterium tuberculosis infection model.
Knudson SE, Awasthi D, Kumar K, Carreau A, Goullieux L, Lagrange S, Vermet H, Ojima I, Slayden RA.
J Antimicrob Chemother. 2015 Nov;70(11):3070-3. doi: 10.1093/jac/dkv226. Epub 2015 Aug 5.
MazF6 toxin of Mycobacterium tuberculosis demonstrates antitoxin specificity and is coupled to regulation of cell growth by a Soj-like protein.
Ramirez MV, Dawson CC, Crew R, England K, Slayden RA.
BMC Microbiol. 2013 Oct 31;13:240. doi: 10.1186/1471-2180-13-240.
Lab: Research Innovation Center (RIC) Room D120