Design, synthesis and evaluation of a series of 5-methoxy-2,3-naphthalimide derivatives as AcrB inhibitors for the reversal of bacterial resistance

Jin, Chaobin; Alenazy, Rawaf; Wang, Yinhu; Mowla, Rumana; Qin, Yinhui; Tan, Jin Quan Eugene; Modi, Natansh D.; Gu, Xinjie; Polyak, Steven W.; Venter, Henrietta; Ma, Shutao

doi:10.1016/j.bmcl.2019.02.003

Cited by 12 publications

(16 citation statements)

References 33 publications

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“…coli AG100 tet ( acrB ++ ) (Figure A) and P. aeruginosa BAA-2795 (Figure B) was negligible as compared to that of untreated cells. In contrast, PAβN and polymyxin B (Gram-negative outer membrane permeabilizer) treated cells showed enhanced fluorescence. Thus, the synergism of the RP1 with the antibiotics observed was not due to the off-target effect of outer membrane permeabilization.…”

Section: Resultsmentioning

confidence: 96%

A Microbe-Derived Efflux Pump Inhibitor of the Resistance-Nodulation-Cell Division Protein Restores Antibiotic Susceptibility in Escherichia coli and Pseudomonas aeruginosa

et al. 2022

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The use of efflux pump inhibitors (EPIs) as potentiators along with the traditional antibiotics assists in the warfare against antibiotic-resistant superbugs. Efflux pumps of the resistance-nodulation-cell division (RND) family play crucial roles in multidrug resistance in Escherichia coli and Pseudomonas aeruginosa. Despite several efforts, clinically useful inhibitors are not available at present. This study describes ethyl 4-bromopyrrole-2-carboxylate (RP1) isolation, an inhibitor of RND transporters from the library of 4000 microbial exudates. RP1 acts synergistically with antibiotics by reducing their minimum inhibitory concentration in strains overexpressing archetype RND transporters (AcrAB-TolC and MexAB-OprM). It also improves the accumulation of Hoechst 33342 and inhibits its efflux (a hallmark of EPI functionality). The antibiotic-RP1 combinations prolong the postantibiotic effects and reduce the mutation prevention concentration of antibiotics. Additionally, from Biolayer Interferometry spectra, it appears that RP1 is bound to AcrB. RP1 displays low mammalian cytotoxicity, no Ca2+ channel inhibitory effects, and reduces the intracellular invasion of E. coli and P. aeruginosa in macrophages. Furthermore, the RP1-levofloxacin combination is nontoxic, well-tolerated, and notably effective in a murine lung infection model. In sum, RP1 is a potent EPI and worthy of further consideration as a potentiator to improve the effectiveness of existing antibiotics.

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Section: Resultsmentioning

confidence: 96%

A Microbe-Derived Efflux Pump Inhibitor of the Resistance-Nodulation-Cell Division Protein Restores Antibiotic Susceptibility in Escherichia coli and Pseudomonas aeruginosa

et al. 2022

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“…This result is not surprising given the potentiation effects thioridazine (35) showed with the knockout as well as the wild-type and its antimicrobial activity against the knockout strain. Despite trifluoperazine (37) sharing these characteristics, it did not appear to damage the outer bacterial membrane as all other compounds besides thioridazine (35) showed similar results to the nitrocefin-only control (Figure 3).…”

Section: T H I S C O N T E N T I S O N L Y L I C E N S E D F O R C O ...mentioning

confidence: 72%

“…Antifungal drugs both butenafine (19) and naftifine (27) showed a 2-fold reduction in MIC with the knockout strain at 16 and 32 μg/mL, respectively, suggesting an additional mechanism of antimicrobial potentiation. Finally, the antipsychotics both thioridazine (35) and trifluoperazine (37) showed a 4-fold reduction in erythromycin MIC at 8 μg/mL as well as showed an antimicrobial activity alone against the knockout strain with the same MIC (32 μg/mL). This suggests another mechanism in addition to efflux inhibition and that these compounds are also substrates of AcrB as they did not have antimicrobial activity alone in the pump-active wild-type strain.…”

Section: T H I S C O N T E N T I S O N L Y L I C E N S E D F O R C O ...mentioning

confidence: 96%

“…The strongest inhibition was seen with apixaban (17), butenafine (19), naftifine (27), rotigotine (33), thioridazine (35), timolol (36), and trifluoperazine (37), which all showed complete inhibition of efflux at both tested concentrations, while meloxicam (26) showed almost full inhibition at both concentrations.…”

Section: T H I S C O N T E N T I S O N L Y L I C E N S E D F O R C O ...mentioning

confidence: 99%

“…Butenafine (19), naftifine (27), pimozide (30), thioridazine (35), and trifluoperazine (37) decreased the MIC of all three antimicrobial substrates: erythromycin, chloramphenicol, and TPP, while ivacaftor (25) enhanced the activity of erythromycin and chloramphenicol, and meloxicam (26) decreased the MIC of erythromycin only (Table 3). While these compounds were effective in reducing the MIC values of several antimicrobials, relatively high concentrations of the compounds were needed to produce these effects.…”

Section: T H I S C O N T E N T I S O N L Y L I C E N S E D F O R C O ...mentioning

confidence: 99%

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Combined Structure- and Ligand-Based Approach for the Identification of Inhibitors of AcrAB-TolC in Escherichia coli

Pisoni,

Semple,

Liu

et al. 2023

ACS Infect. Dis.

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The inhibition of efflux pumps is a promising approach to combating multidrug-resistant bacteria. We have developed a combined structure- and ligand-based model, using OpenEye software, for the identification of inhibitors of AcrB, the inner membrane protein component of the AcrAB-TolC efflux pump in Escherichia coli. From a database of 1391 FDA-approved drugs, 23 compounds were selected to test for efflux inhibition in E. coli. Seven compounds, including ivacaftor (25), butenafine (19), naftifine (27), pimozide (30), thioridazine (35), trifluoperazine (37), and meloxicam (26), enhanced the activity of at least one antimicrobial substrate and inhibited the efflux pump-mediated removal of the substrate Nile Red from cells. Ivacaftor (25) inhibited efflux dose dependently, had no effect on an E. coli strain with genomic deletion of the gene encoding AcrB, and did not damage the bacterial outer membrane. In the presence of a sub-minimum inhibitory concentration (MIC) of the outer membrane permeabilizer colistin, ivacaftor at 1 μg/mL reduced the MICs of erythromycin and minocycline by 4- to 8-fold. The identification of seven potential AcrB inhibitors shows the merits of a combined structure- and ligand-based approach to virtual screening.

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Design and synthesis of novel 4-substituted quinazoline-2-carboxamide derivatives targeting AcrB to reverse the bacterial multidrug resistance

Pisoni

Wang

et al. 2020

Bioorganic Chemistry

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Design, synthesis and evaluation of a series of 5-methoxy-2,3-naphthalimide derivatives as AcrB inhibitors for the reversal of bacterial resistance

Cited by 12 publications

References 33 publications

A Microbe-Derived Efflux Pump Inhibitor of the Resistance-Nodulation-Cell Division Protein Restores Antibiotic Susceptibility in Escherichia coli and Pseudomonas aeruginosa

A Microbe-Derived Efflux Pump Inhibitor of the Resistance-Nodulation-Cell Division Protein Restores Antibiotic Susceptibility in Escherichia coli and Pseudomonas aeruginosa

Combined Structure- and Ligand-Based Approach for the Identification of Inhibitors of AcrAB-TolC in Escherichia coli

Design and synthesis of novel 4-substituted quinazoline-2-carboxamide derivatives targeting AcrB to reverse the bacterial multidrug resistance

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