Blockade of M1 muscarinic acetylcholine receptors modulates the methamphetamine-induced psychomotor stimulant effect

Lee, K.-W.; Tian, Yu-Hua; You, In-Jee; Kwon, Seung-Hwan; Ha, Ri-Ra; Lee, S.-Y.; Kim, H.-C.; Jang, Choon‐Gon

doi:10.1016/j.neuroscience.2008.02.021

Cited by 6 publications

(2 citation statements)

References 69 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…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%

“…Mefloquine was previously identified as an efflux inhibitor with activity against both E. coli and P. aeruginosa ( 35 ), although it had earlier been reported to disrupt the membranes of E. coli ( 40 ). Dicyclomine is an anticholinergic drug that is used in the treatment of irritable bowel syndrome and prevents the methamphetamine-induced efflux of dopamine through eukaryotic transporter proteins ( 38 ). Our data suggest that dicyclomine is an efflux inhibitor.…”

Section: Discussionmentioning

confidence: 99%

See 1 more Smart Citation

New Multidrug Efflux Inhibitors for Gram-Negative Bacteria

Marshall

Lloyd

Lawler

et al. 2020

mBio

View full text Add to dashboard Cite

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.

show abstract