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.

Genome Expression Profiling-Based Identification and Administration Efficacy of Host-Directed Antimicrobial Drugs against Respiratory Infection by Nontypeable Haemophilus influenzae

“…This type of assay has been used to perform a chemical screening of drugs blocking the entry and/or the intracellular growth of Coxiella burnetii, Legionella pneumophila, Brucella abortus, Rickettsia conorii, or Mycobacterium tuberculosis (58,59). Of note, some of the drugs tested here did not alter NTHi adhesion to and invasion of A549 epithelial cells or, if they were found to impair NTHi cell invasion, they did not favor bacterial clearance in vivo.…”

New Role for FDA-Approved Drugs in Combating Antibiotic-Resistant Bacteria

“…The use of host-directed agents for the treatment of antibioticresistant bacteria has recently garnered much attention (5,54,55). Additionally, the repurposing of FDA-approved drugs offers the advantage of readily moving in vitro candidates to in vivo models, since the LD 50 and 50% effective dose (ED 50 ) values are readily available and considerable information about their molecular targets and host pathway interactions is known.…”

“…In recent years, increased focus has been placed on characterizing host mechanisms/pathways exploited by bacteria during pathogenesis. Drugs able to block these pathways represent novel therapeutic options and also reduce the likelihood of the development of resistance, unlike antibiotics (5)(6)(7). Some recent studies utilized such drug-repurposing approaches to identify both novel bactericidal and host-directed drugs as potential therapeutics against pathogens, such as Ebola virus, Borrelia burgdorferi, Coxiella burnetii, and Legionella pneumophila (5,(8)(9)(10).…”

Adrenergic antagonists restrict replication of Legionella

“…One screen for intracellular inhibitors of L. pneumophila did identify carvedilol, a non-selective a1-/b-adrenergic antagonist, as an inhibitor of replication in THP-1 macrophage-like cells (Czyż et al, 2014). We did not observe an effect of carvedilol in our A. castellanii-based assay, possibly reflecting the different host cells used in these assays and perhaps indicating the importance of host-cell features such as receptor sensitivity, membrane permeability and/ or pathogen compartment access of compounds.…”