Addressing the stability of C-capped dipeptide efflux pump inhibitors that potentiate the activity of levofloxacin in Pseudomonas aeruginosa

Renau, Thomas E.; Léger, Roger; Flamme, Eric M.; She, Miles W.; Gannon, Carla L.; Mathias, Kristina; Lomovskaya, Olga; Chamberland, Suzanne; Lee, Ving J.; Ohta, Toshiharu; Nakayama, Kiyoshi; Ishida, Yohei

doi:10.1016/s0960-894x(01)00033-6

Cited by 59 publications

(54 citation statements)

References 10 publications

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“…The first broad-spectrum RND pump inhibitor, MC-207,110 (phenylalanyl-arginyl-β-naphthylamide) was reported to be capable of reversing the MDR phenotype of Pseudomonas aeruginosa and several other Gram-negative bacteria [67,105]. It has also been tested in Acinetobacter baumannii clinical isolates [89,92,107].…”

Section: Efflux Pump Inhibitorsmentioning

confidence: 99%

Multidrug resistant Acinetobacter baumannii--the role of AdeABC (RND family) efflux pump in resistance to antibiotics.

Wieczorek

Sacha²,

Hauschild³

et al. 2008

Folia Histochem Cytobiol.

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Abstract:Acinetobacter baumannii is an opportunistic pathogen which play the more and more greater role in the pathogenicity of the human. It is often attached with the hospital environment, in which is able easily to survive for many days even in adverse conditions. Acinetobacter baumannii is the species responsible for a serious nosocomial infections, especially in the intensive care units. Option of surviving in natural niches, and in the hospital environment could also be associated with the efflux pump mechanisms. Mechanisms of efflux universally appear in all cells (eukaryotic and prokaryotic) and play the physiological important role. In prokaryote, the main functions are evasion of such naturally produced molecules, removal of metabolic products and toxins. These pumps could also be involved in an early stage of infection, such as adhesion to host cells and the colonization. Importantly, they remove commonly used antibiotics from the cell in therapy of infections caused by these bacteria. Efflux pumps exemplify a unique phenomenon in drug resistance: a single mechanism causing resistance against several different classes of antibiotics. In Acinetobacter baumannii, the AdeABC efflux pump, a member of the resistance-nodulation-cell division family (RND), has been well characterized. Aminoglicosides, tetracyclines, erythromycin, chloramphenicol, trimethoprim, fluoroquinolones, some β-lactams, and also recently tigecycline, were found to be substrates for this pump. Drugs, as substrates for the AdeABC pump, can increase the expression of the AdeABC genes, leading to multidrug resistance (MDR). From this reason, treatment failure and death caused by Acinetobacter baumannii infections or underlying diseases are common. Because the AdeABC pump is widespread in Acinetobacter baumannii, similarly to other pumps in Gram-negative and Gram-positive bacteria, exists a need of searching a new therapeutic solutions. Specific efflux inhibitors of pumps (EPIs), including AdeABC inhibitors, could be suppress the activity of pumps and restore the sensitivity of such important bacteria as Acinetobacter baumannii to commonly used antibiotic.

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Section: Efflux Pump Inhibitorsmentioning

confidence: 99%

Multidrug resistant Acinetobacter baumannii--the role of AdeABC (RND family) efflux pump in resistance to antibiotics.

Wieczorek

Sacha²,

Hauschild³

et al. 2008

Folia Histochem Cytobiol.

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“…A family of peptidomimetics, including phenyl-arginine-␤-naphthylamide (PA␤N) (MC-207 110), exhibiting potent inhibition of efflux pumps in P. aeruginosa, has been developed for use as adjunctive therapy (14,(19)(20)(21)(22)(23). 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).…”

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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

163

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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“…A series of dipeptide amide compounds have been identified as efflux pump inhibitors (EPIs) with the ability to broadly inhibit several known multidrug efflux pumps in P. aeruginosa, MexAB-OprM, MexCD-Opr, and MexEF-OprN, and possibly other efflux pumps (10,19,21,22,(34)(35)(36), by competing with antibiotic substrates for binding to the pumps. Devoid of intrinsic antibacterial activity, these inhibitors have been demonstrated to (i) potentiate the activity of FQs and other antibiotics, (ii) reverse acquired FQ resistance attributable to not only efflux mutations but also to target site mutations, and (iii) markedly decrease the frequency with which highly FQ-resistant strains could be selected in vitro (22,34).…”

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confidence: 99%

Use of an Efflux Pump Inhibitor To Determine the Prevalence of Efflux Pump-Mediated Fluoroquinolone Resistance and Multidrug Resistance in Pseudomonas aeruginosa

Kriengkauykiat

Porter

Lomovskaya

et al. 2005

Antimicrob Agents Chemother

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126

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Fluoroquinolone-resistance in Pseudomonas aeruginosa may be due to efflux pump overexpression (EPO) and/or target mutations. EPO can result in multidrug resistance (MDR) due to broad substrate specificity of the pumps. MC-04,124, an efflux pump inhibitor (EPI) shown to significantly potentiate activity of levofloxacin in P. aeruginosa, was used to examine the prevalence of EPO in clinical isolates. MICs were determined for ciprofloxacin, levofloxacin, moxifloxacin, and gatifloxacin with or without EPI and for other antipseudomonal agents by using broth microdilution against P. aeruginosa isolates from adults (n ‫؍‬ 119) and children (n ‫؍‬ 24). The prevalence of the EPO phenotype (>8-fold MIC decrease when tested with EPI) was compared among subgroups with different resistance profiles. The EPO phenotype was more prevalent among levofloxacinresistant than levofloxacin-sensitive strains (61%, 48/79 versus 9%, 6/64). EPO was present in 60% of fluoroquinolone-resistant strains without cross-resistance, while it was present at variable frequencies among strains with cross-resistance to other agents: piperacillin-tazobactam (86%), ceftazidime (76%), cefepime (65%), imipenem (56%), gentamicin (55%), tobramycin (48%), and amikacin (27%). The magnitude of MIC decrease with an EPI paralleled the frequency of which the EPO phenotype was observed in different subgroups. EPI reduced the levofloxacin MIC by as much as 16-fold in eight strains for which MICs were 128 g/ml. Efflux-mediated resistance appears to contribute significantly to fluoroquinolone resistance and MDR in P. aeruginosa. Our data support the fact that increased fluoroquinolone usage can negatively impact susceptibility of P. aeruginosa to multiple classes of antipseudomonal agents.

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Addressing the stability of C-capped dipeptide efflux pump inhibitors that potentiate the activity of levofloxacin in Pseudomonas aeruginosa

Cited by 59 publications

References 10 publications

Multidrug resistant Acinetobacter baumannii--the role of AdeABC (RND family) efflux pump in resistance to antibiotics.

Multidrug resistant Acinetobacter baumannii--the role of AdeABC (RND family) efflux pump in resistance to antibiotics.

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

Use of an Efflux Pump Inhibitor To Determine the Prevalence of Efflux Pump-Mediated Fluoroquinolone Resistance and Multidrug Resistance in Pseudomonas aeruginosa

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