Richard A. Slayden
Associate Professor

Director, Genomics Proteomics Core-RMRCE
Associate Director, Center for Environmental Medicine

Office: 491-2902
Lab: 491-1925 Fax: 491-1815
Email: Richard.Slayden@colostate.edu
Office: B208 Microbiology Building
Lab: B203 Microbiology Building

Degrees

B.S., Colorado State University
Ph.D., Colorado State University

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 defences 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.

Refereed Journal Articles (http://publicationslist.org/richard.slayden)

Kathleen England, Christopher am Ende, Hao Lu, Todd J. Sullivan, Nicole L. Marlenee, Richard A. Bowen, Susan E. Knudson, Dennis L. Knudson, Peter J. Tonge and Richard A. Slayden. (2009) Substituted diphenyl ethers as a broad-spectrum platform for the development of chemotherapeutics for the treatment of tularaemia. Journal of Antimicrobial Chemotherapy. Sep 4 [Epub ahead of print].

Diana L. Williams, Richard A. Slayden, Amol Amin, Alejandra N. Martinez, Tana L. Pittman, Alex Mira, Anirban Mitra, Valakunja Nagaraja, Norman E. Morrison, Milton Moraes and Thomas P. Gillis. (2009) Implications of high level pseudogene transcription in Mycobacterium leprae. BMC Genomics. 10(1):397.

Mercedes Gonzalez-Juarrero, Luke C. Kingry, Diane J. Ordway, Marcela Henao-Tamayo, Marisa Harton, Randall J. Basaraba, William H. Hanneman, Ian M. Orme and Richard A. Slayden. (2009) Immune Response to Mycobacterium tuberculosis and Identification of Molecular Markers of Disease. American Journal of Respiratory Cell and Molecular Biology. 40:398-409.

Richard A. Slayden and John T. Belisle. (2009) Morphological Features and Signature Gene Response Elicited by Inactivation of FtsI in Mycobacterium tuberculosis. Journal of Antimicrobial Chemotherapy. 63(3):451-7.

Rakesh K. Dhiman, Sebabrata Mahapatra, Richard A. Slayden, Melissa E. Boyne, Anne Lenaerts, Jerald C. Hinshaw, Shiva K. Angala, Delphi Chatterjee, Kallolmay Biswas, Prabagaran Narayanasamy, Michio Kurosu, and Dean C. Crick. (2009) Menaquinone Synthesis is Critical for Maintaining Mycobacterial Viability During Exponential Growth and Recovery from Non-Replicating Persistence. Molecular Microbiology. 72(1):85-97.

Hao Lu, Kathleen England, Chris am Ende, James J. Truglio, Sylvia Luckner, B. Gopal Reddy, Nikki Marlenee, Susan E. Knudson, Dennis L. Knudson, Richard A. Bowen, Caroline Kisker, Richard A. Slayden and Peter J. Tonge. (2009) Slow-Onset Inhibition of the FabI Enoyl Reductase from Francisella tularensis : Residence Time and In Vivo Activity. ACS Chemical Biology. 4(3):221-31.

Dianqing Sun, Michael S. Scherman, Victoria Jones, Julian G. Hurdle, Lisa K. Woolhiser, Susan E. Knudson, Anne J. Lenaerts, Richard A. Slayden, Micahel R. McNeil and Richard E. Lee. (2009) Discovery, Synthesis and Biological Evaluation of Piperidinol Analogs with Anti-tuberculosis Activity. Bioorganic & Medicinal Chemistry. 17(10):3588-94.

Laurel Respicio, Pravin A. Nair, Qing Huang, Burcu Anil, Sylvia Tracz, James J. Truglio, Caroline Kisker, Daniel P. Raleigh, Iwao Ojima, Dennis L. Knudson, Peter J. Tonge and Richard A. Slayden. (2008) Characterizing Septum Inhibition in Mycobacterium tuberculosis for Novel Drug Discovery. Tuberculosis. 88: 420-429.

Christopher W. am Ende, Susan E. Knudson, Nina Liu, James Childs, Todd J. Sullivan, Melissa Boyne, Hua Xu, Dennis L. Knudson, Francis Johnson, Charles A. Peloquin, Richard A. Slayden and Peter J. Tonge. (2008) Synthesis and in vitro activity of B-ring modified diaryl ether InhA inhibitors: Anti-mycobacterial agents with improved Lipinski parameters. Bioorganic Medicinal Chemistry Letters. 18: 3029-3033.

Melissa E. Boyne, Todd J. Sullivan, Christopher W. amEnde, Hao Lu, Veronica Gruppo, Darragh Heaslip, Anita Amin, Delphi Chatterjee, Anne Lenaerts, Peter J. Tonge and Richard A. Slayden. (2007) Targeting fatty acid biosynthesis for the development of novel chemotherapeutics against Mycobacterium tuberculosis: Evaluation of A-ring modified diphenyl ethers as high affinity InhA inhibitors. Antimicrobial Agents and Chemotherapy. 51(10):3562-7.

Qing Huang, Peter J. Tonge, Richard A. Slayden, Teruo Kirikae and Iwao Ojima. (2007) FtsZ: A Novel Target for Tuberculosis Drug Discovery. Current Topics in Medicinal Chemistry. 7(5):527-43.

Peter J. Tonge, Caroline Kisker and Richard A. Slayden. (2007) Development of Modern InhA Inhibitors to Combat Drug Resistant Strains of Mycobacterium tuberculosis. Current Topics in Medicinal Chemistry. 7(5):489-98.

Richard A. Slayden, Dennis L. Knudson, John T. Belisle. (2006) Identification of cell cycle regulators in Mycobacterium tuberculosis by inhibition of septum formation and global transcriptional analysis. Microbiology. 152:1789-97.

Nathan A. Groathouse, Amol Amin, A., Maria Angela Marques, John S. Spencer, Robert Gelber, Dennis L. Knudson, John T. Belisle, Patrick J. Brennan, Richard A. Slayden. (2006) Use of protein microarrays to define the humoral immune response in leprosy patients and identification of disease-state-specific antigenic profiles. Infection and Immunity. 74(11):6458-66.

Nathan A. Groathouse, Susan E. Brown, Dennis L. Knudson, Patrick J. Brennan, Richard A. Slayden. (2006) Isothermal amplification and molecular typing of the obligate intracellular pathogen Mycobacterium leprae isolated from tissues of unknown origin. Journal of Clinical Microbiology. 44(4):1502-8.

Todd J. Sullivan, James J. Truglio, Melissa E. Boyne, Polina Novichenok, Xujie Zhang, Christopher F. Stratton, Huei-Jiun Li, Tejinder Kaur, Amol Amin, Francis Johnson, Richard A. Slayden, Caroline Kisker, Peter J. Tonge. (2006) High Affinity InhA Inhibitors with Activity against Drug-Resistant Strains of Mycobacterium tuberculosis. ACS Chemical Biology. 1(1), 43-53.

Mark J. Sartain, Richard A. Slayden, Krishna K. Singh, Suman Laal, John T. Belisle. (2006) Disease state differentiation and identification of tuberculosis biomarkers via native antigen array profiling. Molecular and Cellular Proteomics. 5(11):2102-2113.

Qing Huang, Fumiko Kirikae, Teruo Kirikae, Antonella Pepe, Amol Amin, Laurel Respicio, Richard A. Slayden, Peter J. Tonge, Iwao Ojima. (2006) Targeting FtsZ for antituberculosis drug discovery: noncytotoxic taxanes as novel antituberculosis agents. Journal of Medicinal Chemistry. 49(2):463-6.

Benjawan Phetsuksiri, Mary Jackson, Hataichanock Scherman, Michael McNeil, Gurdyal S. Besra, Alain R. Baulard, Richard A. Slayden, Andrea E. DeBarber, Clifton E. Barry, 3rd, Mark S. Baird, Dean C. Crick, Patrick J. Brennan. (2003) Unique mechanism of action of the thiourea drug isoxyl on Mycobacterium tuberculosis. Journal of Biological Chemistry. 278(52): 53123-30.

Richard Lee, Marina Protopopova, Emma Crooks, Richard A. Slayden, Clifton E. Barry 3rd. (2003) Combinatorial lead optimization of [1,2]-diamines based on ethambutol as potential antituberculosis preclinical candidates. Journal of Combinatorial Chemistry. 5(2):172-87.

Richard A. Slayden and Clifton E. Barry, 3rd. (2002) The role of KasA and KasB in the Biosynthesis of Meromycolic Acids in Mycobacterium tuberculosis and Isoniazid Resistance. Tuberculosis. 82 (4/5):149-60.

Ida Rosenkrands, Richard A. Slayden, Jane Crawford, Claus Aagaard, Clifton E. Barry, 3rd, Peter Andersen. (2002) The Hypoxic response of Mycobacterium tuberculosis studied by metabolic labeling and proteome analysis of cellular and extracellular proteins. Journal of Bacteriology. 183(13):3485-91.

Richard A. Slayden, Richard E. Lee, Clifton E. Barry, 3rd. (2000) Isoniazid Effects Multiple Components of the Type II Fatty Acid Synthase System of Mycobacterium tuberculosis. Molecular Microbiology. 38(3):514-25.

Marcel A. Behr, Benjamin G. Shroeder, Jacueline N. Brinkman, Richard A. Slayden, Clifton E. Barry, 3rd. (2000) Point Mutation in mma3 gene is responsible for impaired methoxymycolic acid production in BCG strains obtained after 1927. Journal of Bacteriology. 182:3394-9.

Linda Wang, Richard A. Slayden, Clifton E. Barry, 3rd, Jun Liu. (2000) Cell Wall Structure of a Mutant of Mycobacterium smegmatis Defective in the Biosynthesis of Mycolic Acids. Journal of Biological Chemistry. 275(10):7224-9.

Richard A. Slayden, Clifton E. Barry, 3rd. (2000) Genetics of Isoniazid Resistance in Mycobacterium tuberculosis. Microbes and Infection. 2(6):659-69.

Clifton E. Barry, 3rd, Richard A. Slayden, Andrea E. Sampson, Richard E. Lee. (2000) The use of Genomics and Combinatorial Chemistry in the Development of New Antimycobacterial Drugs. Biochemical Pharmacology. 59:221-31.

Khisimuzi Mdluli, Richard A. Slayden, YaQi Zhu, Srinivas Rhamaswamy, Xi Pan, David Mead, Deborah Crane, James M. Musser, Clifton E. Barry 3rd. (1998) Inhibition of a Mycobacterium tuberculosis Keto-acyl ACP Synthase by Isoniazid. Science. 280:1607-10.

Clifton E. Barry, 3rd, Richard E. Lee, Khisimuzi Mdluli, Andrea Sampson, Benjamin. G. Schroeder, Richard A. Slayden, Ying Yuan. (1998) Mycolic Acids: Structure, Biosynthesis and Physiological Functions. Progress in Lipid Research. 37(2/3):143-79.

Clifton E. Barry, 3rd, Richard A. Slayden, Khisimuzi Mdluli. (1998) Mechanisms of Isoniazid Resistance in Mycobacterium tuberculosis. Drug Resistance Updates. 1:128-34.

Richard A. Slayden, Richard E. Lee, Jason W. Armour, Andrea M. Cooper, Ian A. Orme, Patrick J. Brennan, Gurdyl S. Besra. (1996) Anti-Mycobacterial Action of Thiolactomycin: An Inhibitor of Fatty Acid and Mycolic Acid Synthesis. Antimicrobial Agents and Chemotherapy. 40(12):2813-39.

Katarina Mikosova, Richard A. Slayden, Gurdyl S. Besra, Patrick J. Brennan. (1995) Biogenesis of the Mycobacterial Cell Wall and the Site of Action of Ethambutol. Antimicrobial Agents and Chemotherapy. 39(11):2484-89.

Gurdyl S. Besra, Todd Sievert, Richard E. Lee, Richard A. Slayden, Patrick J. Brennan, Kuni Takayama. (1994) Identification of the Apparent Carrier in Mycolic Acid Synthesis. Proceeding in the National Academy of Sciences, USA. 91:12735-39.

Refereed Chapters in Books

Richard A. Slayden, Dean Crick, Michael M. McNeil, Patrick J. Brennan. (2003) Genomics in Tuberculosis Drug Discovery. Pp. 111-134. In The Role of Genomics in Antibacterial Drug Discovery, Marcel Dekker, Inc.

Richard A. Slayden and Clifton E. Barry, 3rd. (2001) Analysis of the Lipids of Mycobacterium tuberculosis. Pp. 229-246. In T. Parish and N. Stoker (ed) Mycobacterium tuberculosis Protocols, Humana Press Inc. New Jersey

Refereed Proceedings

Richard A. Slayden. Genome, Transcriptome and Proteome of M. leprae: Application to Basic Clinical Questions. 16th International Leprosy Congress. International Journal of Leprosy. 2003