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Richard Slayden

Associate Professor
Associate Director,Center for Environmental Medicine

Office: D116 Research Innovation Center
Office Phone: (970)491-2902
Email: richard.slayden@colostate.edu

Research Interests

My laboratory uses a multi-disciplinary approach to drug development and the discovery of preclinical lead compounds with efficacy against priority A-C bacterial pathogens, in particular multi-drug resistant M. tuberculosis, F. tularensis, B. pseudomallei and Y. pestis, as well as medically important pathogens including S. pneumonia. Areas of research emphasis fall into the broad subjects of cell cycle regulation, bacterial differentiation, and host-pathogen interaction. These areas of interest are predicated on the idea that success of bacterial pathogens relies on their ability to adapt to the dynamic and complex environments encountered during infection and different stages of disease. The hypothesis is that the encountered conditions instigate changes in the bacteria that result in the development of specialized populations capable of evading host defenses and eliciting a drug tolerant phenotype. Importantly, in order for a drug to have efficacy it needs to target the unique and active metabolic activities of the pathogen that are occurring during infection and at different states of disease.

Cell division, cell cycle regulation, bacterial differentiation and non-replicating persistence

It is clear from the culmination of the studies ongoing in my laboratory that cell cycle progression and population differentiation relies on a choreographed series of metabolic changes and, contrary to current dogma, non-replicating persistence or latency is a continual active process. The physiology of the bacilli is heterogeneous and is the result of a complex regulatory network that allows this bacterium to adapt and cope with environmental stress without requiring extensive new macromolecular synthesis. Recognition of phenotypic adaptation in bacteria has led to the radical multicellular concept I refer to as Phenomic Potential, which is the principal that the bacterial chromosome encodes more functions than can be accommodated in any single cell at any given time, but through intricate regulatory control mechanisms individual cells can be "tailored" to diverse conditions leading to a selective advantage for the whole bacterial population.

Our studies have implicated a number of previously unknown regulatory elements that modulate gene expression, influence protein synthesis and modulate protein activity in establishing a persistent state with the ability to resume growth. Specifically, transcriptional, translational, non-translation and post-translational regulatory elements work in concert to rapidly modulate gene expression and adapt the protein repertoire in response to altered growth conditions.

Host response to infection

Upon exposure to a pathogen, the host employs both the innate and acquired immune responses to combat infection and control dissemination. While the general features of the host response is known, the specific mechanisms employed to control dissemination of specific pathogens is limited. Accordingly, to obtain information about the host response and the different stages of disease and extent of dissemination to infection we are investigating the whole genome transcriptional response in the M. tuberculosis and F. tularensis animal models of infection.

These studies have provided information regarding the dynamics of the immune response at the molecular level and the role of dissemination in pathogenesis. Notably, these studies are not limited to the host response, they also include the bacterial response, thus allowing for a direct connection to be established between the host environment and bacterial metabolism.

Preclinical drug development

Our hypothesis is that highly conserved essential proteins are good broad-spectrum targets for novel drug discovery against bacterial pathogens. Accordingly we have chosen to target conserved essential protein components of the bacterial type II fatty acid synthase pathway, cell division among others. Historically in vitro potency has little correlation to in vivo efficacy; that is many compounds are very active against whole bacteria, but lack efficacy in animal models of infection. The incorporation of pathogen physiology in the context of infection allows us to focus our development efforts to those pathways involved in pathogen survival at specific time of infection.

A significant limitation to development of new drugs against novel or underexploited targets is not having lead structural classes [with activity] as a starting point for the drug development process. We have addressed this in two ways; (1) to build on known pharmacophores with activity against proteins of similar structure and (2) to employ virtual screening to identify new structural classes of compounds that may be suitable for drug development using our compound library that totals more than 10 million structures, assembled from a variety of individual libraries.

It has been our experience that the information gained from screening many compounds for efficacy against in vivo challenge is indispensable for informing and driving the medicinal chemistry efforts. Thus, our screening strategy involves progressing compounds into animal models of infection as rapidly as possible. The most potent compounds are then progressed into more advanced studies with the animal model of infection. This process results in the identification of compounds with in vitro potency, in vivo efficacy and the appropriate physiochemical properties including toxicity and deliverability for preclinical candidacy. Importantly, the convergence of chemistry and genomic information has fostered a parallel-screening approach, which incorporates information gained from primary and secondary, target and whole cell-based approaches, toxicity, and pre-animal physiochemical evaluation to prioritize progression into animal models of infection.

Currently a hurdle to preclinical drug development is formulation and delivery of compounds. The majority of novel inhibitors have LogP values in the insoluble range and are therefore difficult to deliver consistently, and limits their bioavailability. We employ alternative routes of delivery including aerosol, and formulation to enhance drug uptake, PK/PD parameters, and toxicity to enhance efficacy.

Together, these areas of research investigate aspects of bacteria such as phenotypic variation and adaptation that takes place during an infection, and characterization of the corresponding host environment provides the opportunity to develop novel chemotherapeutics targeted to specific clinically important metabolic pathways, that take advantage of the pathogen-host relationship. It is the overall goal to incorporate information obtained from studying a diverse set of human pathogens using state of the art technologies in a multidisciplinary fashion to identify and develop novel inhibitors with potency against metabolically privileged bacterial populations. In deed, the broad themes of one bacterial pathogen or group of pathogens with similar lifestyles can serve as a foundation for investigations with other bacterial pathogens.

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