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Browsing by Author "Pearce, Camron, author"

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    Inhalational antibiotic therapy for treatment of chronic pulmonary Mycobacterium abscessus disease in mice
    (Colorado State University. Libraries, 2019) Pearce, Camron, author; Gonzalez-Juarrero, Mercedes, advisor; Jackson, Mary, committee member; Volckens, John, committee member
    Mycobacterium abscessus (M. abscessus) is a nontuberculous mycobacterium that causes chronic pulmonary infections. Due to M. abscessus's intrinsic antibiotic resistance, treatment is often complex with low cure rates. Tigecycline, a glycylcycline class antibiotic, demonstrates bactericidal effects against M. abscessus without eliciting bacterial resistance mechanisms, however, this antibiotic requires intravenous administration and causes significant side effects that limit its use. Here, we tested the hypothesis that tigecycline administered via inhalation has the potential to maximize the bactericidal effect while reducing side effects. GM-CSF knockout mice with pulmonary M. abscessus infection were treated by intrapulmonary tigecycline aerosols in 0.25 mg, 1.25 mg, and 2.50 mg doses for 28 days. Assessment of pulmonary bacterial burden after full treatment duration shows that inhaled tigecycline is highly effective, dose-dependent, and well tolerated. We concluded that inhaled tigecycline represents a viable treatment option for M. abscessus pulmonary disease. Future studies should address the pharmacokinetics, and ultimately, translation into clinical trials.
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    Therapeutic efficacy of antimalarial drugs targeting DosRS signaling in Mycobacterium abscessus
    (Colorado State University. Libraries, 2022-02-23) Belardinelli, Juan Manuel, author; Verma, Deepshikha, author; Li, Wei, author; Avanzi, Charlotte, author; Wiersma, Crystal J., author; Williams, John T., author; Johnson, Benjamin K., author; Zimmerman, Matthew, author; Whittel, Nicholas, author; Angala, Bhanupriya, author; Wang, Han, author; Jones, Victoria, author; Dartois, Veronique, author; de Moura, Vinicius C. N., author; Gonzalez-Juarrero, Mercedes, author; Pearce, Camron, author; Schenkel, Alan R., author; Malcolm, Kenneth C., author; Nick, Jerry A., author; Charman, Susan A., author; Wells, Timothy N. C., author; Podell, Brendan K., author; Vennerstrom, Jonathan L., author; Ordway, Diane J., author; Abramovitch, Robert B., author; Jackson, Mary, author
    A search for alternative Mycobacterium abscessus treatments led to our interest in the two-component regulator DosRS, which, in Mycobacterium tuberculosis, is required for the bacterium to establish a state of nonreplicating, drug-tolerant persistence in response to a variety of host stresses. We show here that the genetic disruption of dosRS impairs the adaptation of M. abscessus to hypoxia, resulting in decreased bacterial survival after oxygen depletion, reduced tolerance to a number of antibiotics in vitro and in vivo, and the inhibition of biofilm formation. We determined that three antimalarial drugs or drug candidates, artemisinin, OZ277, and OZ439, can target DosS-mediated hypoxic signaling in M. abscessus and recapitulate the phenotypic effects of genetically disrupting dosS. OZ439 displayed bactericidal activity comparable to standard-of-care antibiotics in chronically infected mice, in addition to potentiating the activity of antibiotics used in combination. The identification of antimalarial drugs as potent inhibitors and adjunct inhibitors of M. abscessus in vivo offers repurposing opportunities that could have an immediate impact in the clinic.