title: Host-directed antimicrobial drugs with broad-spectrum efficacy against intracellular bacterial pathogens.
abstract: We sought a new approach to treating infections by intracellular bacteria, namely, by altering host cell functions that support their growth. We screened a library of 640 Food and Drug Administration (FDA)-approved compounds for agents that render THP-1 cells resistant to infection by four intracellular pathogens. We identified numerous drugs that are not antibiotics but were highly effective in inhibiting intracellular bacterial growth with limited toxicity to host cells. These compounds are likely to target three kinds of host functions: (i) G protein-coupled receptors, (ii) intracellular calcium signals, and (iii) membrane cholesterol distribution. The compounds that targeted G protein receptor signaling and calcium fluxes broadly inhibited Coxiella burnetii, Legionella pneumophila, Brucella abortus, and Rickettsia conorii, while those directed against cholesterol traffic strongly attenuated the intracellular growth of C. burnetii and L. pneumophila. These pathways probably support intracellular pathogen growth so that drugs that perturb them may be therapeutic candidates. Combining host- and pathogen-directed treatments is a strategy to decrease the emergence of drug-resistant intracellular bacterial pathogens. Importance: Although antibiotic treatment is often successful, it is becoming clear that alternatives to conventional pathogen-directed therapy must be developed in the face of increasing antibiotic resistance. Moreover, the costs and timing associated with the development of novel antimicrobials make repurposed FDA-approved drugs attractive host-targeted therapeutics. This paper describes a novel approach of identifying such host-targeted therapeutics against intracellular bacterial pathogens. We identified several FDA-approved drugs that inhibit the growth of intracellular bacteria, thereby implicating host intracellular pathways presumably utilized by bacteria during infection.
authors: Daniel M
authors: DM
authors: Czyż
authors: Howard Taylor Ricketts Laboratory, University of Chicago, Argonne National Laboratory, Lemont, Illinois, USA Department of Microbiology, University of Chicago, Chicago, Illinois, USA.
authors: Lakshmi-Prasad
authors: LP
authors: Potluri
authors: Howard Taylor Ricketts Laboratory, University of Chicago, Argonne National Laboratory, Lemont, Illinois, USA Department of Biochemistry and Molecular Biology, University of Chicago, Chicago, Illinois, USA.
authors: Neeta
authors: N
authors: Jain-Gupta
authors: Howard Taylor Ricketts Laboratory, University of Chicago, Argonne National Laboratory, Lemont, Illinois, USA Department of Microbiology, University of Chicago, Chicago, Illinois, USA.
authors: Sean P
authors: SP
authors: Riley
authors: Howard Taylor Ricketts Laboratory, University of Chicago, Argonne National Laboratory, Lemont, Illinois, USA Department of Microbiology, University of Chicago, Chicago, Illinois, USA.
authors: Juan J
authors: JJ
authors: Martinez
authors: Department of Biochemistry and Molecular Biology, University of Chicago, Chicago, Illinois, USA.
authors: Theodore L
authors: TL
authors: Steck
authors: Sean
authors: S
authors: Crosson
authors: hashuman@uchicago.edu.
authors: Howard A
authors: HA
authors: Shuman
authors: Department of Microbiology, University of Chicago, Chicago, Illinois, USA.
authors: Joëlle E
authors: JE
authors: Gabay
mesh_terms: D000900:Anti-Bacterial Agents / Q000494:pharmacology*; D002003:Brucella abortus / Q000187:drug effects* / Q000472:pathogenicity; D002460:Cell Line; D016997:Coxiella burnetii / Q000187:drug effects* / Q000472:pathogenicity; D006801:Humans; D016952:Legionella pneumophila / Q000187:drug effects* / Q000472:pathogenicity; D020114:Rickettsia conorii / Q000187:drug effects* / Q000472:pathogenicity
chemical_list: D000900:Anti-Bacterial Agents