MexAB-OprM specific efflux pump inhibitors in Pseudomonas aeruginosa. Part 4: Addressing the problem of poor stability due to photoisomerization of an acrylic acid moiety

Nakayama, Kiyoshi; Kuru, Noriko; Ohtsuka, Masaya; Yokomizo, Yoshihiro; Sakamoto, A.; Kawato, Haruko C.; Yoshida, Kenichi; Ohta, Toshiharu; Hoshino, Kazuki; Akimoto, Katsuya; Itoh, Junko; Ishida, Hiroko; Cho, Aesop; Palme, Monica H.; Zhang, Jason Z.; Lee, Ving J.; Watkins, William J.

doi:10.1016/j.bmcl.2004.03.007

Cited by 46 publications

(13 citation statements)

References 10 publications

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“…From the original family of diamine EPIs, such as the peptidomimetics described above, several other structural classes have been explored in extensive design, synthesis and characterization studies . Nakayama et al reported compound 75 (Figure ) as the first example of a MexAB‐OprM specific EPI .…”

Section: Efflux Pump Inhibitors Of Selected Clinically Relevant Pathomentioning

confidence: 99%

“…Several compounds were then prepared with improved biological properties, including activity, stability, and reduced toxicity . For example, vinyl tetrazoles with 2‐piperidinyl substituents, such as in 78 (Figure ), and acrylic acid derivatives bearing aryl residues in place of piperidine, such as in 79 (Figure ), were prepared.…”

Section: Efflux Pump Inhibitors Of Selected Clinically Relevant Pathomentioning

confidence: 99%

“…Compound 78 showed high potency in vitro, but the solubility was very low. In contrast, 79 had improved solubility and showed a reasonable safety profile in an acute toxicity assay, but displayed only moderate activity in vivo . Compounds 76 to 79 were all considered as MexAB‐OprM specific EPIs …”

Section: Efflux Pump Inhibitors Of Selected Clinically Relevant Pathomentioning

confidence: 99%

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Efflux pump inhibitors of clinically relevant multidrug resistant bacteria

Lamut

Mašič

Kikelj

et al. 2019

Medicinal Research Reviews

145

116

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Bacterial infections are an increasingly serious issue worldwide. The inability of existing therapies to treat multidrug‐resistant pathogens has been recognized as an important challenge of the 21st century. Efflux pumps are important in both intrinsic and acquired bacterial resistance and identification of small molecule efflux pump inhibitors (EPIs), capable of restoring the effectiveness of available antibiotics, is an active research field. In the last two decades, much effort has been made to identify novel EPIs. However, none of them has so far been approved for therapeutic use. In this article, we explore different structural families of currently known EPIs for multidrug resistance efflux systems in the most extensively studied pathogens (NorA in Staphylococcus aureus, AcrAB‐TolC in Escherichia coli, and MexAB‐OprM in Pseudomonas aeruginosa). Both synthetic and natural compounds are described, with structure‐activity relationship studies and optimization processes presented systematically for each family individually. In vitro activities against selected test strains are presented in a unifying manner for all the EPIs described, together with the most important toxicity, pharmacokinetic and in vivo efficacy data. A critical evaluation of lead‐likeness characteristics and the potential for clinical development of the most promising inhibitors of the three efflux systems is described. This overview of EPIs is a good starting point for the identification of novel effective antibacterial drugs.

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Section: Efflux Pump Inhibitors Of Selected Clinically Relevant Pathomentioning

confidence: 99%

Section: Efflux Pump Inhibitors Of Selected Clinically Relevant Pathomentioning

confidence: 99%

Section: Efflux Pump Inhibitors Of Selected Clinically Relevant Pathomentioning

confidence: 99%

See 1 more Smart Citation

Efflux pump inhibitors of clinically relevant multidrug resistant bacteria

Lamut

Mašič

Kikelj

et al. 2019

Medicinal Research Reviews

145

116

View full text Add to dashboard Cite

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“…Pyridopyrimidines and arylpiperazines have also been assayed as EPIs of MDR pumps and major efforts have been performed for their optimization (Nakayama et al, 2004a, b; Yoshida et al, 2006a, b, 2007). Differing to the previously described dipeptide amides, that only impede the action of the antibiotics they compete, pyridopyrimidines increase the susceptibility to all substrates of the efflux pumps, indicating a different mechanism of action (Lomovskaya and Bostian, 2006).…”

Section: Inhibitors Of Resistance Determinantsmentioning

confidence: 99%

The intrinsic resistome of bacterial pathogens

Olivares¹,

Bernardini²,

et al. 2013

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Intrinsically resistant bacteria have emerged as a relevant health problem in the last years. Those bacterial species, several of them with an environmental origin, present naturally low-level susceptibility to several drugs. It has been proposed that intrinsic resistance is mainly the consequence of the impermeability of cellular envelopes, the activity of multidrug efflux pumps or the lack of appropriate targets for a given family of drugs. However, recently published articles indicate that the characteristic phenotype of susceptibility to antibiotics of a given bacterial species depends on the concerted activity of several elements, what has been named as intrinsic resistome. These determinants comprise not just classical resistance genes. Other elements, several of them involved in basic bacterial metabolic processes, are of relevance for the intrinsic resistance of bacterial pathogens. In the present review we analyze recent publications on the intrinsic resistomes of Escherichia coli and Pseudomonas aeruginosa. We present as well information on the role that global regulators of bacterial metabolism, as Crc from P. aeruginosa, may have on modulating bacterial susceptibility to antibiotics. Finally, we discuss the possibility of searching inhibitors of the intrinsic resistome in the aim of improving the activity of drugs currently in use for clinical practice.

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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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MexAB-OprM specific efflux pump inhibitors in Pseudomonas aeruginosa. Part 4: Addressing the problem of poor stability due to photoisomerization of an acrylic acid moiety

Cited by 46 publications

References 10 publications

Efflux pump inhibitors of clinically relevant multidrug resistant bacteria

Efflux pump inhibitors of clinically relevant multidrug resistant bacteria

The intrinsic resistome of bacterial pathogens

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

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