Host-Directed Drug Targeting of Factors Hijacked by Pathogens

Schwegmann, Anita; Brombacher, Frank

doi:10.1126/scisignal.129re8

Cited by 113 publications

(92 citation statements)

References 123 publications

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“…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.…”

Section: Discussionmentioning

confidence: 99%

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

Andersson

Fitts

Kirtley

et al. 2016

Antimicrob Agents Chemother

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h Antibiotic resistance in medically relevant bacterial pathogens, coupled with a paucity of novel antimicrobial discoveries, represents a pressing global crisis. Traditional drug discovery is an inefficient and costly process; however, systematic screening of Food and Drug Administration (FDA)-approved therapeutics for other indications in humans offers a rapid alternative approach. In this study, we screened a library of 780 FDA-approved drugs to identify molecules that rendered RAW 264.7 murine macrophages resistant to cytotoxicity induced by the highly virulent Yersinia pestis CO92 strain. Of these compounds, we identified 94 not classified as antibiotics as being effective at preventing Y. pestis-induced cytotoxicity. A total of 17 prioritized drugs, based on efficacy in in vitro screens, were chosen for further evaluation in a murine model of pneumonic plague to delineate if in vitro efficacy could be translated in vivo. Three drugs, doxapram (DXP), amoxapine (AXPN), and trifluoperazine (TFP), increased animal survivability despite not exhibiting any direct bacteriostatic or bactericidal effect on Y. pestis and having no modulating effect on crucial Y. pestis virulence factors. These findings suggested that DXP, AXPN, and TFP may modulate host cell pathways necessary for disease pathogenesis. Finally, to further assess the broad applicability of drugs identified from in vitro screens, the therapeutic potential of TFP, the most efficacious drug in vivo, was evaluated in murine models of Salmonella enterica serovar Typhimurium and Clostridium difficile infections. In both models, TFP treatment resulted in increased survivability of infected animals. Taken together, these results demonstrate the broad applicability and potential use of nonantibiotic FDA-approved drugs to combat respiratory and gastrointestinal bacterial pathogens.

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Section: Discussionmentioning

confidence: 99%

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

Andersson

Fitts

Kirtley

et al. 2016

Antimicrob Agents Chemother

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“…Different viruses, in particular those representing related viral families, frequently rely on an overlapping set of host cell factors and pathways for their replication (1,2). As substantiated by recent evidence (4,5), many host requirements are conserved among related viruses, increasing the possibility for broad-spectrum antiviral activity.…”

mentioning

confidence: 98%

“…Therapeutic targeting of host factors required for virus replication has emerged as a novel concept of antiviral therapy that has high promise to advance beyond some of these limitations (1)(2)(3). Different viruses, in particular those representing related viral families, frequently rely on an overlapping set of host cell factors and pathways for their replication (1,2).…”

mentioning

confidence: 99%

Dual Myxovirus Screen Identifies a Small-Molecule Agonist of the Host Antiviral Response

Yan

Krumm

Sun

et al. 2013

J Virol

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f As we are confronted with an increasing number of emerging and reemerging viral pathogens, the identification of novel pathogen-specific and broad-spectrum antivirals has become a major developmental objective. Targeting of host factors required for virus replication presents a tangible approach toward obtaining novel hits with a broadened indication range. However, the identification of developable host-directed antiviral candidates remains challenging. We describe a novel screening protocol that interrogates the myxovirus host-pathogen interactome for broad-spectrum drug candidates and simultaneously probes for conventional, pathogen-directed hits. With resource efficiency and pan-myxovirus activity as the central developmental parameters, we explored coscreening against two distinct, independently traceable myxoviruses in a single-well setting. Having identified a pair of unrelated pathogenic myxoviruses (influenza A virus and measles virus) with comparable replication kinetics, we observed unimpaired coreplication of both viruses, generated suitable firefly and Renilla luciferase reporter constructs, respectively, and validated the protocol for up to a 384-well plate format. Combined with an independent counterscreen using a recombinant respiratory syncytial virus luciferase reporter, implementation of the protocol identified candidates with a broadened antimyxovirus profile, in addition to pathogen-specific hits. Mechanistic characterization revealed a newly discovered broadspectrum lead that does not block viral entry but stimulates effector pathways of the innate cellular antiviral response. In summary, we provide proof of concept for the efficient discovery of broad-spectrum myxovirus inhibitors in parallel to para-and orthomyxovirus-specific hit candidates in a single screening campaign. The newly identified compound provides a basis for the development of a novel broad-spectrum small-molecule antiviral class.

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“…Furthermore, the standard drugs that are used to treat leishmaniasis, such as SSG, are toxic and have poor patient compliance because of long treatment times ranging from 3 to 5 wk and the requirement for parenteral administration. Therefore, treating infectious diseases by targeting host pathways that are critical for pathogen invasion and survival has recently been considered as a viable option for developing new therapeutic agents against infectious diseases (31). Some studies have reported that targeting host molecules inhibits intracellular growth of bacteria and parasites such as Plasmodium in the host cell in vitro (32).…”

Section: Discussionmentioning

confidence: 99%

Critical role for phosphoinositide 3-kinase gamma in parasite invasion and disease progression of cutaneous leishmaniasis

Cummings

Barbi

Reville

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

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Obligate intracellular pathogens such as Leishmania specifically target host phagocytes for survival and replication. Phosphoinositide 3-kinase γ (PI3Kγ), a member of the class I PI3Ks that is highly expressed by leukocytes, controls cell migration by initiating actin polymerization and cytoskeletal reorganization, which are processes also critical for phagocytosis. In this study, we demonstrate that class IB PI3K, PI3Kγ, plays a critical role in pathogenesis of chronic cutaneous leishmaniasis caused by L. mexicana. Using the isoform-selective PI3Kγ inhibitor, AS-605240 and PI3Kγ gene-deficient mice, we show that selective blockade or deficiency of PI3Kγ significantly enhances resistance against L. mexicana that is associated with a significant suppression of parasite entry into phagocytes and reduction in recruitment of host phagocytes as well as regulatory T cells to the site of infection. Furthermore, we demonstrate that AS-605240 is as effective as the standard antileishmanial drug sodium stibogluconate in treatment of cutaneous leishmaniasis caused by L. mexicana. These findings reveal a unique role for PI3Kγ in Leishmania invasion and establishment of chronic infection, and demonstrate that therapeutic targeting of host pathways involved in establishment of infection may be a viable strategy for treating infections caused by obligate intracellular pathogens such as Leishmania.

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Host-Directed Drug Targeting of Factors Hijacked by Pathogens

Cited by 113 publications

References 123 publications

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

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

Dual Myxovirus Screen Identifies a Small-Molecule Agonist of the Host Antiviral Response

Critical role for phosphoinositide 3-kinase gamma in parasite invasion and disease progression of cutaneous leishmaniasis

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