Dataset Information

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.

SUBMITTER: Czyz DM

PROVIDER: S-EPMC4128363 | biostudies-literature | 2014 Jul

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

Host-directed antimicrobial drugs with broad-spectrum efficacy against intracellular bacterial pathogens.

Czyż Daniel M DM Potluri Lakshmi-Prasad LP Jain-Gupta Neeta N Riley Sean P SP Martinez Juan J JJ Steck Theodore L TL Crosson Sean S Shuman Howard A HA Gabay Joëlle E JE

mBio 20140729 4

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 li ...[more]

PMID: 25073644

Similar Datasets

Project description:BACKGROUND: The emergence of drug-resistant pathogen strains and new infectious agents pose major challenges to public health. A promising approach to combat these problems is to target the host's genes or proteins, especially to discover targets that are effective against multiple pathogens, i.e., host-oriented broad-spectrum (HOBS) drug targets. An important first step in the discovery of such drug targets is the identification of host responses that are commonly perturbed by multiple pathogens. RESULTS: In this paper, we present a methodology to identify common host responses elicited by multiple pathogens. First, we identified host responses perturbed by each pathogen using a gene set enrichment analysis of publicly available genome-wide transcriptional datasets. Then, we used biclustering to identify groups of host pathways and biological processes that were perturbed only by a subset of the analyzed pathogens. Finally, we tested the enrichment of each bicluster in human genes that are known drug targets, on the basis of which we elicited putative HOBS targets for specific groups of bacterial pathogens. We identified 84 up-regulated and three down-regulated statistically significant biclusters. Each bicluster contained a group of pathogens that commonly dysregulated a group of biological processes. We validated our approach by checking whether these biclusters correspond to known hallmarks of bacterial infection. Indeed, these biclusters contained biological process such as inflammation, activation of dendritic cells, pro- and anti- apoptotic responses and other innate immune responses. Next, we identified biclusters containing pathogens that infected the same tissue. After a literature-based analysis of the drug targets contained in these biclusters, we suggested new uses of the drugs Anakinra, Etanercept, and Infliximab for gastrointestinal pathogens Yersinia enterocolitica, Helicobacter pylori kx2 strain, and enterohemorrhagic Escherichia coli and the drug Simvastatin for hematopoietic pathogen Ehrlichia chaffeensis. CONCLUSIONS: Using a combination of automated analysis of host-response gene expression data and manual study of the literature, we have been able to suggest host-oriented treatments for specific bacterial infections. The analyses and suggestions made in this study may be utilized to generate concrete hypothesis on which gene sets to probe further in the quest for HOBS drug targets for bacterial infections. All our results are available at the following supplementary website: http://bioinformatics.cs.vt.edu/ murali/supplements/2013-kidane-plos-one.

Project description:Objectives: Therapies being safe, effective and not vulnerable to develop resistance are highly desirable to counteract bacterial infections. Host-directed therapeutics is an alternative to conventional antibiotics based on perturbing host pathways subverted by pathogens during their life cycle by the use of host-directed drugs to counteract microbial infections. This study sought to identify cellular genes and pathways differentially expressed during airways epithelial infection by nontypable Haemophilus influenzae (NTHi). NTHi is an opportunistic pathogen that is an important cause of exacerbation of chronic obstructive pulmonary disease (COPD). Based on the proposed relationship between NTHi intracellular location and persistence, the antimicrobial potential of a panel of drugs perturbing host pathways used by NTHi to enter epithelial cells was investigated. Methods: We screened for host genes differentially expressed upon infection by the clinical isolate NTHi375 by analyzing A549 cell whole genome expression profiling, and identified a panel of host target candidates which were pharmacologically modulated. Interfering drugs were tested for their bactericidal effect, cytotoxicity, effect on the interplay NTHi-epithelial cell, and effect on NTHi respiratory infection in vivo, by assessing lung bacterial loads in a murine intranasal infection model. Results: The sirtuin-1 activator resveratrol showed a bactericidal effect against NTHi; the PDE4 inhibitor rolipram showed therapeutic efficacy by lowering NTHi375 counts both intracellularly and in the lungs of infected mice. Conclusions: PDE4 inhibition is currently prescribed in COPD; resveratrol is a geroprotector attractive for COPD treatment by preventing lung aging. This work provides evidence for the antimicrobial potential of rolipram and resveratrol against NTHi respiratory infection. Haemophilus influenzae clinical strain NTHi375 induced gene expression in A549 human type II pneumocyte cell line was measured at 2 h post-infection. Non infected cells were used as a control. Four independent experiments were performed for each condition.

Dataset Information

Host-directed antimicrobial drugs with broad-spectrum efficacy against intracellular bacterial pathogens.

Publications

Host-directed antimicrobial drugs with broad-spectrum efficacy against intracellular bacterial pathogens.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets