Host-Directed Antimicrobial Drugs with Broad-Spectrum Efficacy against Intracellular Bacterial Pathogens

Czyż, Daniel M.; Potluri, Lakshmi-Prasad; Jain-Gupta, Neeta; Riley, Sean P.; Martinez, Juan J.; Steck, Theodore L.; Crosson, Sean; Shuman, Howard A.; Gabay, Joëlle E.

doi:10.1128/mbio.01534-14

Title: Host-Directed Antimicrobial Drugs with Broad-Spectrum Efficacy against Intracellular Bacterial Pathogens

Journal Article · Tue Jul 29 00:00:00 EDT 2014 · mBio (Online)

DOI:https://doi.org/10.1128/mbio.01534-14· OSTI ID:1626134

Czyż, Daniel M. ^[1]; Potluri, Lakshmi-Prasad ^[1]; Jain-Gupta, Neeta ^[2]; Riley, Sean P. ^[1]; Martinez, Juan J. ^[1]; Steck, Theodore L. ^[3]; Crosson, Sean ^[2]; Shuman, Howard A. ^[1]; Gabay, Joëlle E. ^[4]

Univ. of Chicago, IL (United States). Howard Taylor Ricketts Lab.; Argonne National Lab. (ANL), Argonne, IL (United States); Univ. of Chicago, IL (United States). Dept. of Microbiology
Univ. of Chicago, IL (United States). Howard Taylor Ricketts Lab.; Argonne National Lab. (ANL), Argonne, IL (United States); Univ. of Chicago, IL (United States). Dept. of Biochemistry and Molecular Biology
Univ. of Chicago, IL (United States). Dept. of Biochemistry and Molecular Biology
Univ. of Chicago, IL (United States). Dept. of Microbiology

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.

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Research Organization:: Argonne National Laboratory (ANL), Argonne, IL (United States)

Sponsoring Organization:: USDOE Office of Science (SC), Biological and Environmental Research (BER). Biological Systems Science Division; National Institutes of Health (NIH)

Grant/Contract Number:: AC02-06CH11357; 1-U54-AI-057153; 5RO1 AI23549

OSTI ID:: 1626134

Journal Information:: mBio (Online), Vol. 5, Issue 4; ISSN 2150-7511

Publisher:: American Society for Microbiology (ASM)Copyright Statement

Country of Publication:: United States

Language:: English

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