Melioidosis caused by the gram-negative bacterium Burkholderia pseudomallei is remarkably resistant to most classes of antibiotics. Even after months of treatment with antibacterials relatively effective in vitro, between 6 and 20% of individuals suffer from relapsed B. pseudomallei infections, indicating that this pathogen alters its patterns of antibacterial susceptibility in response to cues encountered in the host. Data presented in our application have identified nitrosative stress and anaerobiosis as two host conditions that promote B. pseudomallei drug tolerance. Our goal is to identify antibacterials that improve the effectiveness of therapy against melioidosis and identify novel drug targets. We hypothesize that nitric oxide and low oxygen tensions drive B. pseudomallei into an altered metabolic and drug-tolerant state. To address this hypothesis we will determine the: 1) molecular adaptations that mediate resistance of B. pseudomallei to nitrosative stress;2) adaptive mechanisms that facilitate anaerobic survival of B. pseudomallei;and 3) contribution of nitrosative stress and anaerobic stasis to antibacterial tolerance. Our recently developed bacteriological techniques, genetics, microarray transcriptional profiling, cell culture systems and biochemical assays will help us identify adaptive and metabolic pathways that promote tolerance of 8. pseudomallei to antibacterials used in humans suffering from melioidosis. In collaboration with Dr. Steven Dow at Colorado State University, we will determine how antinitrosative defenses and metabolic networks contribute to the pathogenesis of 8. pseudomallei in a murine model of melioidosis. In addition, we will continue with our efforts to identify antibacterials effective against nonrespiring 8. pseudomallei. Towards this goal, we have already determined that drugs that target anaerobes are very effective against nonrespiring 8. pseudomallei while drugs that kill aerobic bacteria fail. The therapeutic potential of anaerobic antibacterials against nonrespiring 8. pseudomallei will be studied in a murine model of chronic melioidosis. These studies are within the scope of the RMRCE to discover novel antibacterial targets and to develop antibacterials that improve efficacy against the widespread clinical antibiotic resistance of melioidosis. Our investigations synergize with the research proposed by Dr. Schweizer in project RP 2.1 to study the natural resistance of 8. pseudomallei to antibacterials tested under aerobic conditions in a murine model of acute infection

Public Health Relevance

Melioidosis caused by Burkholderia bacteria kills a high percentage of infected people, making this microbe a highly coveted agent for bioterrorism. Treatment is hampered by natural and host-induced resistance of Burkholderia to antibiotics. It is imperative we find new antibacterials that eliminate the infection from infected individuals. Our investigations will identify and test drugs capable of curing infections with Burkholderia.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Specialized Center--Cooperative Agreements (U54)
Project #
5U54AI065357-08
Application #
8375705
Study Section
Special Emphasis Panel (ZAI1-DDS-M)
Project Start
Project End
Budget Start
2012-05-01
Budget End
2013-04-30
Support Year
8
Fiscal Year
2012
Total Cost
$353,085
Indirect Cost
$74,293
Name
Colorado State University-Fort Collins
Department
Type
DUNS #
785979618
City
Fort Collins
State
CO
Country
United States
Zip Code
80523
Skyberg, Jerod A; Lacey, Carolyn A (2017) Hematopoietic MyD88 and IL-18 are essential for IFN-?-dependent restriction of type A Francisella tularensis infection. J Leukoc Biol 102:1441-1450
Plumley, Brooke A; Martin, Kevin H; Borlee, Grace I et al. (2017) Thermoregulation of Biofilm Formation in Burkholderia pseudomallei Is Disrupted by Mutation of a Putative Diguanylate Cyclase. J Bacteriol 199:
Furuta, Yousuke; Komeno, Takashi; Nakamura, Takaaki (2017) Favipiravir (T-705), a broad spectrum inhibitor of viral RNA polymerase. Proc Jpn Acad Ser B Phys Biol Sci 93:449-463
Podnecky, Nicole L; Rhodes, Katherine A; Mima, Takehiko et al. (2017) Mechanisms of Resistance to Folate Pathway Inhibitors in Burkholderia pseudomallei: Deviation from the Norm. MBio 8:
Pettey, W B P; Carter, M E; Toth, D J A et al. (2017) Constructing Ebola transmission chains from West Africa and estimating model parameters using internet sources. Epidemiol Infect 145:1993-2002
Rhodes, Katherine A; Schweizer, Herbert P (2016) Antibiotic resistance in Burkholderia species. Drug Resist Updat 28:82-90
Lehman, Stephanie S; Mladinich, Katherine M; Boonyakanog, Angkana et al. (2016) Versatile nourseothricin and streptomycin/spectinomycin resistance gene cassettes and their use in chromosome integration vectors. J Microbiol Methods 129:8-13
Rico, Amber B; Phillips, Aaron T; Schountz, Tony et al. (2016) Venezuelan and western equine encephalitis virus E1 liposome antigen nucleic acid complexes protect mice from lethal challenge with multiple alphaviruses. Virology 499:30-39
Calvert, Amanda E; Dixon, Kandice L; Piper, Joseph et al. (2016) A humanized monoclonal antibody neutralizes yellow fever virus strain 17D-204 in vitro but does not protect a mouse model from disease. Antiviral Res 131:92-9
Westover, Jonna B; Sefing, Eric J; Bailey, Kevin W et al. (2016) Low-dose ribavirin potentiates the antiviral activity of favipiravir against hemorrhagic fever viruses. Antiviral Res 126:62-8

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