Neurotransmitter System-Targeting Drugs Antagonize Growth of the Q Fever Agent, Coxiella burnetii, in Human Cells

Coxiella burnetii is a highly infectious, intracellular, Gram-negative bacterial pathogen that causes human Q fever, an acute flu-like illness that can progress to chronic endocarditis. C. burnetii is transmitted to humans via aerosols and has long been considered a potential biological warfare agent. Although antibiotics, such as doxycycline, effectively treat acute Q fever, a recently identified antibiotic-resistant strain demonstrates the ability of C. burnetii to resist traditional antimicrobials, and chronic disease is extremely difficult to treat with current options. These find-ings highlight the need for new Q fever therapeutics, and repurposed drugs that target eukaryotic functions to prevent bacterial replication are of increasing interest in infectious disease. To identify this class of anti-C. burnetii therapeutics, we screened a library of 727 FDA-approved or late-stage clinical trial compounds using a human macrophage-like cell model of infection. Eighty-eight compounds inhibited bacterial replication, including known antibiotics, antipsychotic or antidepressant treatments, antihistamines, and several additional compounds used to treat a variety of conditions. The majority of identified anti-C. burnetii compounds target host neurotransmitter system components. Serotoninergic, dopaminergic, and adrenergic components are among the most highly represented targets and potentially regulate macrophage activation, cytokine production, and autophagy. Overall, our screen identified multiple host-directed compounds that can be pursued for potential use as anti-C. burnetii drugs. IMPORTANCE Coxiella burnetii causes the debilitating disease Q fever in humans. This infection is difficult to treat with current antibiotics and can progress to long-term, potentially fatal infection in immunocompromised individuals or when treatment is delayed. Here, we identified many new potential treatment options in the form of drugs that are either FDA approved or have been used in late-stage clinical trials and target human neurotransmitter systems. These compounds are poised for future characterization as nontraditional anti-C. burnetii therapies.