MexAB-OprM specific efflux pump inhibitors in Pseudomonas aeruginosa. Part 6: Exploration of aromatic substituents

Yoshida, Kenichi; Nakayama, Kiyoshi; Yokomizo, Yoshihiro; Ohtsuka, Masaya; Takemura, Makoto; Hoshino, Kazuki; Kanda, Hiroko; Namba, Kei; Nitanai, Hironobu; Zhang, Jason Z.; Lee, Ving J.; Watkins, William J.

doi:10.1016/j.bmc.2006.08.037

Cited by 55 publications

(53 citation statements)

References 13 publications

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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.…”

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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

165

153

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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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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

165

153

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“…Although compounds in this series were validated using in vivo infection models [4,5,7], nephrotoxicity across the series prevented further development [8]. A second example of EPI drug development involves a series of pyridopyrimidine EPIs that culminated in D13-9001, a lead compound which was advanced to preclinical development [9-15]. The pyridopyrimidine EPIs are specific for the MexAB efflux pump of P. aeruginosa, but are not active against the MexXY pump of P. aeruginosa , which was likely a factor in the apparent cessation of development in 2007 [16].…”

Section: Introductionmentioning

confidence: 99%

Optimization of a novel series of pyranopyridine RND efflux pump inhibitors

Aron

Opperman

2016

Current Opinion in Microbiology

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The rise of multidrug resistant (MDR) Gram-negative pathogens complicates our ability to treat bacterial infections with antibiotics. MDR efflux pumps play a major role in the acquisition and expression of the MDR phenotype. The major MDR efflux pumps in the Gram-negative pathogens are the resistance-nodulation-division (RND) superfamily pumps. Efflux pump inhibitors (EPIs) that target RND superfamily pumps could play an important role in the clinic as an adjunctive therapy to increase antibiotic efficacy, decrease resistance, and attenuate virulence in Gram-negative pathogens. Here, we review recent advances in the discovery and structurally enabled optimization of a novel series of RND-targeting pyranopyridine EPIs currently in the early stages of lead optimization.

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“…Amongst the family of heterocyclic compounds, the heterocycles with N, S and O atoms have attracted the attention of chemical research due to their wide spectrum of biological activities. Morpholine has its unique position in heterocyclic chemistry, and its derivatives are gaining considerable importance due to diverse biological activities such as antimalarial (Singh et al, 2006), antibacterial (Hirokawa et al, 2009), antimicrobial (Fung et al, 2001;Yoshida et al, 2006), antidepressant (Takeuchi et al, 1997), antiproliferative (Li et al, 2009), hypocholesterolemic (Chrysselis et al, 2000), antileukemic (Szulawska et al, 2007;Jakubowska et al, 2008), antibiotic (Piestrzeniewicz et al, 2004) etc. Similarly, piperazine is also a biodynamic heterosystem, and continues to be a target of interest due to its presence in a number of natural and synthetic drugs.…”

Section: Introductionmentioning

confidence: 99%

Synthesis and antimicrobial activity of morpholinyl/piperazinylbenzothiazines

2011

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Structurally diverse morpholinyl/piperazinylbenzothiazines have been synthesized in quantitative yields by the reaction of substituted 1,4-benzothiazines with morpholine/N-(2-hydroxyethyl)piperazine. 1,4-Benzothiazines were prepared by the reaction of substituted 2-aminobenzenethiols with b-ketoesters. The structures of the synthesized compounds were confirmed by their analytical and spectroscopic data. The synthesized compounds were evaluated for their antimicrobial activity against bacterial species; E. coli and Bacillus cereus. Some of the synthesized compounds have shown significant activity against microorganisms.

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MexAB-OprM specific efflux pump inhibitors in Pseudomonas aeruginosa. Part 6: Exploration of aromatic substituents

Cited by 55 publications

References 13 publications

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

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

Optimization of a novel series of pyranopyridine RND efflux pump inhibitors

Synthesis and antimicrobial activity of morpholinyl/piperazinylbenzothiazines

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