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.
Discovery of a novel type IIb RelBE toxin-antitoxin system in Mycobacterium tuberculosis defined by co-regulation with an antisense RNA.
Dawson CC, Cummings JE, Starkey JM, Slayden RA.
Mol Microbiol. 2022 Jun;117(6):1419-1433. doi: 10.1111/mmi.14917. Epub 2022 May 24. PMID: 35526138
Improved non-redundant species screening panels for benchmarking the performance of new investigational antibacterial candidates against Category A and B priority pathogens.
JAC Antimicrob Resist. 2022 Mar 24;4(2):dlac028. doi: 10.1093/jacamr/dlac028. eCollection 2022 Apr.PMID: 35350133
A Novel Glucocorticoid and Androgen Receptor Modulator Reduces Viral Entry and Innate Immune Inflammatory Responses in the Syrian Hamster Model of SARS-CoV-2 Infection.
Rocha SM, Fagre AC, Latham AS, Cummings JE, Aboellail TA, Reigan P, Aldaz DA, McDermott CP, Popichak KA, Kading RC, Schountz T, Theise ND, Slayden RA, Tjalkens RB.
Front Immunol. 2022 Feb 16;13:811430. doi: 10.3389/fimmu.2022.811430. eCollection 2022. PMID: 35250984
Rational design of a new antibiotic class for drug-resistant infections.
Durand-Reville TF, Miller AA, O’Donnell JP, Wu X, Sylvester MA, Guler S, Iyer R, Shapiro AB, Carter NM, Velez-Vega C, Moussa SH, McLeod SM, Chen A, Tanudra AM, Zhang J, Comita-Prevoir J, Romero JA, Huynh H, Ferguson AD, Horanyi PS, Mayclin SJ, Heine HS, Drusano GL, Cummings JE, Slayden RA, Tommasi RA.
Nature. 2021 Sep;597(7878):698-702. doi: 10.1038/s41586-021-03899-0. Epub 2021 Sep 15. PMID: 34526714
Toxin-antitoxin systems and regulatory mechanisms in Mycobacterium tuberculosis.
Slayden RA, Dawson CC, Cummings JE.
Pathog Dis. 2018 Jun 1;76(4). doi: 10.1093/femspd/fty039. Review.
Lab Principal Investigator [PI]
Research Associate IV
Research Associate I
Anatomic Pathology Resident
Graduate Research Assistant
Lab: Research Innovation Center (RIC) Room D120