MexAB-OprM-Specific efflux pump inhibitors in Pseudomonas aeruginosa. Part 1: Discovery and early strategies for lead optimization

Nakayama, Kiyoshi; Ishida, Yohei; Ohtsuka, Masaya; Kawato, Haruko C.; Yoshida, Ken-ichi; Yokomizo, Yoshihiro; Hosono, Shigeru; Ohta, Toshiharu; Hoshino, Kazuki; Ishida, Hiroko; Yoshida, Kumi; Renau, Thomas E.; Léger, Roger; Zhang, Jason Z.; Lee, Ving J.; Watkins, William J.

doi:10.1016/j.bmcl.2003.07.024

Cited by 73 publications

(47 citation statements)

References 28 publications

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“…When 50 clinical isolates were tested, the presence of the EPI reduced the MIC 90 by about 16-fold. Research on derivatives of this compound is attempting to identify more potent inhibitors that may be used in the clinical setting in the future [62][63][64][65][66].…”

Section: Efflux Pump Inhibitorsmentioning

confidence: 99%

Role of efflux mechanisms on fluoroquinolone resistance in Streptococcus pneumoniae and Pseudomonas aeruginosa

Zhanel

Hoban

Schurek

et al. 2004

International Journal of Antimicrobial Agents

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Section: Efflux Pump Inhibitorsmentioning

confidence: 99%

Role of efflux mechanisms on fluoroquinolone resistance in Streptococcus pneumoniae and Pseudomonas aeruginosa

Zhanel

Hoban

Schurek

et al. 2004

International Journal of Antimicrobial Agents

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“…58 It is a key reaction to synthesize important class of intermediates in the cosmetic and pharmaceutical industries 59 due to their properties as enzyme 15 inhibitors, antitumor, anti-inflammatory, and antibacterial agents. [60][61][62][63][64] Besides the importance of the Knoevenagel condensation as a synthetic organic method, another relevant characteristic of this reaction is its ability to measure the number and the relative strength of base active sites, by reacting a series 20 of methylenic compounds with different pK a values. 65 Thus, the Knoevenagel condensation between benzaldehyde and substrates with different pK a values (with distinct activated methylenic groups), such as malononitrile (MN, 3a) (pK a ≈7), ethyl cyanoacetate (ECA, 3b) (pK a ≈9), ethyl acetoacetate (pK a ≈11) and 25 diethyl malonate (DEM, 3c) (pK a ≈13) are extensively performed in order to characterize base catalysts.…”

Section: One Pot-deacetalization-knoevenagel Reactionmentioning

confidence: 99%

Designing bifunctional acid–base mesoporous hybrid catalysts for cascade reactions

Gianotti

Díaz

Velty

et al. 2013

Catal. Sci. Technol.

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“…Some of these inhibitors were validated using in vivo infection models (20,21,23); however, they were abandoned because of toxicity (24). In addition, a series of pyridopyrimidine EPIs specific for the MexAB efflux pump of P. aeruginosa advanced to the preclinical stage (12,(25)(26)(27)(28)(29)(30). In this paper, we describe the discovery and in vitro characterization of MBX2319, a novel pyranopyridine inhibitor of the RND class AcrAB-TolC efflux pump in E. coli and other pathogens of the Enterobacteriaceae.…”

mentioning

confidence: 99%

Characterization of a Novel Pyranopyridine Inhibitor of the AcrAB Efflux Pump of Escherichia coli

Opperman

Kwasny

Kim

et al. 2014

Antimicrob Agents Chemother

160

154

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cMembers of the resistance-nodulation-division (RND) family of efflux pumps, such as AcrAB-TolC of Escherichia coli, play major roles in multidrug resistance (MDR) in Gram-negative bacteria. A strategy for combating MDR is to develop efflux pump inhibitors (EPIs) for use in combination with an antibacterial agent. Here, we describe MBX2319, a novel pyranopyridine EPI with potent activity against RND efflux pumps of the Enterobacteriaceae. MBX2319 decreased the MICs of ciprofloxacin (CIP), levofloxacin, and piperacillin versus E. coli AB1157 by 2-, 4-, and 8-fold, respectively, but did not exhibit antibacterial activity alone and was not active against AcrAB-TolC-deficient strains. MBX2319 (3.13 M) in combination with 0.016 g/ml CIP (minimally bactericidal) decreased the viability (CFU/ml) of E. coli AB1157 by 10,000-fold after 4 h of exposure, in comparison with 0.016 g/ml CIP alone. In contrast, phenyl-arginine-␤-naphthylamide (PA␤N), a known EPI, did not increase the bactericidal activity of 0.016 g/ml CIP at concentrations as high as 100 M. MBX2319 increased intracellular accumulation of the fluorescent dye Hoechst 33342 in wild-type but not AcrAB-TolC-deficient strains and did not perturb the transmembrane proton gradient. MBX2319 was broadly active against Enterobacteriaceae species and Pseudomonas aeruginosa. MBX2319 is a potent EPI with possible utility as an adjunctive therapeutic agent for the treatment of infections caused by Gram-negative pathogens. Multidrug resistance (MDR) in Gram-negative pathogens, including Enterobacteriaceae, Pseudomonas aeruginosa, Acinetobacter spp., and Stenotrophomonas maltophilia, poses a significant threat to the effective treatment of infections caused by these organisms (1-4). The MDR threat has been exacerbated by the recent decrease in commercial efforts to discover and develop new antibacterial agents. In addition, antibacterial agents that have been introduced recently into the clinic or are in development, such as daptomycin, gemifloxacin, telithromycin, and telavancin, are not active against Gram-negative pathogens. Recently FDAapproved agents with activity against Gram-negative bacteria include tigecycline and doripenem. While tigecycline is active against bacteria producing a tetracycline-specific pump in vitro, it is pumped out rapidly by the ubiquitous multidrug pumps, and its pharmacokinetic properties limit its use for treating urinary tract infections (UTIs) and bloodstream infections (5), as will the evolution of resistance during therapy (6). Clearly, novel strategies for effectively treating infections caused by MDR Gram-negative pathogens are urgently needed.The MDR phenotype has been attributed to both acquired and intrinsic mechanisms of resistance. However, the resistance-nodulation-division (RND) efflux pumps of Gram-negative bacteria play a major role in MDR. Because of their broad substrate specificity, overexpression of these efflux pumps results in decreased susceptibility to a diverse array of antibacterial agents and biocides (7). The major ef...

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MexAB-OprM-Specific efflux pump inhibitors in Pseudomonas aeruginosa. Part 1: Discovery and early strategies for lead optimization

Cited by 73 publications

References 28 publications

Role of efflux mechanisms on fluoroquinolone resistance in Streptococcus pneumoniae and Pseudomonas aeruginosa

Role of efflux mechanisms on fluoroquinolone resistance in Streptococcus pneumoniae and Pseudomonas aeruginosa

Designing bifunctional acid–base mesoporous hybrid catalysts for cascade reactions

Characterization of a Novel Pyranopyridine Inhibitor of the AcrAB Efflux Pump of Escherichia coli

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