Evaluation of a Library of FDA-Approved Drugs for Their Ability To Potentiate Antibiotics against Multidrug-Resistant Gram-Negative Pathogens

Hind, Charlotte K.; Dowson, Christopher G.; Sutton, J. Mark; Jackson, Thomas R.; Clifford, Melanie; Garner, R. Colin; Czaplewski, Lloyd G.

doi:10.1128/aac.00769-19

Cited by 15 publications

(19 citation statements)

References 15 publications

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“…The diphenylbutylpiperidine-class of drugs has also been studied, revealing host-directed effects of Pimozide against both facultative and obligate intracellular pathogens, Listeria monocytogenes and Toxoplasma gondii respectively 67 , 68 . Also, Fluspirilene has been shown to potentiate antimicrobial activity against several bacteria, but only in a direct antibiotic manner 69 , 70 . Despite these observations, we found no direct antimicrobial effect of Fluspirilene (or Pimozide) on either Mtb or Stm .…”

Section: Discussionmentioning

confidence: 99%

Repurposing diphenylbutylpiperidine-class antipsychotic drugs for host-directed therapy of Mycobacterium tuberculosis and Salmonella enterica infections

Heemskerk

Korbee

Esselink

et al. 2021

Sci Rep

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The persistent increase of multidrug-resistant (MDR) Mycobacterium tuberculosis (Mtb) infections negatively impacts Tuberculosis treatment outcomes. Host-directed therapies (HDT) pose an complementing strategy, particularly since Mtb is highly successful in evading host-defense by manipulating host-signaling pathways. Here, we screened a library containing autophagy-modulating compounds for their ability to inhibit intracellular Mtb-bacteria. Several active compounds were identified, including two drugs of the diphenylbutylpiperidine-class, Fluspirilene and Pimozide, commonly used as antipsychotics. Both molecules inhibited intracellular Mtb in pro- as well as anti-inflammatory primary human macrophages in a host-directed manner and synergized with conventional anti-bacterials. Importantly, these inhibitory effects extended to MDR-Mtb strains and the unrelated intracellular pathogen, Salmonella enterica serovar Typhimurium (Stm). Mechanistically Fluspirilene and Pimozide were shown to regulate autophagy and alter the lysosomal response, partly correlating with increased bacterial localization to autophago(lyso)somes. Pimozide’s and Fluspirilene’s efficacy was inhibited by antioxidants, suggesting involvement of the oxidative-stress response in Mtb growth control. Furthermore, Fluspirilene and especially Pimozide counteracted Mtb-induced STAT5 phosphorylation, thereby reducing Mtb phagosome-localized CISH that promotes phagosomal acidification. In conclusion, two approved antipsychotic drugs, Pimozide and Fluspirilene, constitute highly promising and rapidly translatable candidates for HDT against Mtb and Stm and act by modulating the autophagic/lysosomal response by multiple mechanisms.

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Section: Discussionmentioning

confidence: 99%

Repurposing diphenylbutylpiperidine-class antipsychotic drugs for host-directed therapy of Mycobacterium tuberculosis and Salmonella enterica infections

Heemskerk

Korbee

Esselink

et al. 2021

Sci Rep

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“…For example, a comparison of Escherichia coli and Staphylococcus aureus clinical isolates reported 5-FU minimum inhibitory concentrations that differ by 100-fold: 250 μ g/ml versus 2 to 4 μ g/ml, respectively ( 25 ). The heightened sensitivity of Gram-positive bacteria to 5-FU and other drugs ( 30 , 31 ) is consistent with their lack of a protective outer membrane barrier ( 32 , 33 ).…”

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confidence: 58%

An Oral Fluorouracil Prodrug, Capecitabine, Mitigates a Gram-Positive Systemic Infection in Mice

2021

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“…Three of the identified compounds from the Prestwick library have been previously identified as efflux inhibitors in bacteria ( 33 – 35 ), thus validating the screen, and a further 40 from the Roche library were characterized as inhibitors of multidrug efflux in Gram-negative bacteria. A further four of the identified compounds from the Prestwick library have been reported to potentiate antibiotic activity but without a mechanism being identified ( 18 , 36 ), while four other compounds identified by our screen are known to inhibit transport in eukaryotic cells ( 32 , 37 – 39 ).…”

Section: Discussionmentioning

confidence: 87%

“…A study by Hind et al used the Prestwick Chemical Library to identify compounds that overcome multidrug resistance by any mechanism (36). Of the 14 compounds identified as "antibiotic resistance breakers," four (auranofin, daunorubicin, thioridazine, and zidovudine) were also identified by the ramAp:gfp reporter screen.…”

Section: Discussionmentioning

confidence: 99%

New Multidrug Efflux Inhibitors for Gram-Negative Bacteria

Marshall

Lloyd

Lawler

et al. 2020

mBio

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Active efflux of antibiotics preventing their accumulation to toxic intracellular concentrations contributes to clinically relevant multidrug resistance. Inhibition of active efflux potentiates antibiotic activity, indicating that efflux inhibitors could be used in combination with antibiotics to reverse drug resistance. Expression of ramA by Salmonella enterica serovar Typhimurium increases in response to efflux inhibition, irrespective of the mode of inhibition. We hypothesized that measuring ramA promoter activity could act as a reporter of efflux inhibition. A rapid, inexpensive, and high-throughput green fluorescent protein (GFP) screen to identify efflux inhibitors was developed, validated, and implemented. Two chemical compound libraries were screened for compounds that increased GFP production. Fifty of the compounds in the 1,200-compound Prestwick chemical library were identified as potential efflux inhibitors, including the previously characterized efflux inhibitors mefloquine and thioridazine. There were 107 hits from a library of 47,168 proprietary compounds from L. Hoffmann La Roche; 45 were confirmed hits, and a dose response was determined. Dye efflux and accumulation assays showed that 40 Roche and three Prestwick chemical library compounds were efflux inhibitors. Most compounds had specific efflux-inhibitor-antibiotic combinations and/or species-specific synergy in antibiotic disc diffusion and checkerboard assays performed with Escherichia coli, Pseudomonas aeruginosa, Acinetobacter baumannii, and Salmonella Typhimurium. These data indicate that both narrow-spectrum and broad-spectrum combinations of efflux inhibitors with antibiotics can be found. Eleven novel efflux inhibitor compounds potentiated antibiotic activities against at least one species of Gram-negative bacteria, and data revealing an E. coli mutant with loss of AcrB function suggested that these are AcrB inhibitors. IMPORTANCE Multidrug-resistant Gram-negative bacteria pose a serious threat to human and animal health. Molecules that inhibit multidrug efflux offer an alternative approach to resolving the challenges caused by antibiotic resistance, by potentiating the activity of old, licensed, and new antibiotics. We have developed, validated, and implemented a high-throughput screen and used it to identify efflux inhibitors from two compound libraries selected for their high chemical and pharmacological diversity. We found that the new high-throughput screen is a valuable tool to identify efflux inhibitors, as evidenced by the 43 new efflux inhibitors described in this study.

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Evaluation of a Library of FDA-Approved Drugs for Their Ability To Potentiate Antibiotics against Multidrug-Resistant Gram-Negative Pathogens

Cited by 15 publications

References 15 publications

Repurposing diphenylbutylpiperidine-class antipsychotic drugs for host-directed therapy of Mycobacterium tuberculosis and Salmonella enterica infections

Repurposing diphenylbutylpiperidine-class antipsychotic drugs for host-directed therapy of Mycobacterium tuberculosis and Salmonella enterica infections

An Oral Fluorouracil Prodrug, Capecitabine, Mitigates a Gram-Positive Systemic Infection in Mice

New Multidrug Efflux Inhibitors for Gram-Negative Bacteria

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