MexAB-OprM specific efflux pump inhibitors in Pseudomonas aeruginosa. Part 2: achieving activity in vivo through the use of alternative scaffolds

Nakayama, Kiyoshi; Ishida, Yohei; Ohtsuka, Masaya; Kawato, Haruko C.; Yoshida, Kenichi; Yokomizo, Yoshihiro; Ohta, Toshiharu; Hoshino, Kazuki; Otani, Tomoyuki; Kurosaka, Yuichi; Yoshida, Kumi; Ishida, Hiroko; Lee, Ving J.; Renau, Thomas E.; Watkins, William J.

doi:10.1016/j.bmcl.2003.07.027

Cited by 53 publications

(22 citation statements)

References 19 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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“…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%

“…It also showed reduced binding to serum proteins. Although 76 was not the most potent analog, it displayed the best in vivo efficacy with 100% survival rate after 7 days at a 50 mg/kg dose, in combination with a 15 mg/kg dose of levofloxacin in a murine neutropenic sepsis model with PAM1723 . Extensive SAR studies were performed, leading to the discovery that incorporation of a hydrophobic moiety at the 2‐position of the pyridopyrimidinone scaffold significantly enhances activity due to its occupying an additional hydrophobic binding pocket.…”

Section: Efflux Pump Inhibitors Of Selected Clinically Relevant Pathomentioning

confidence: 99%

Efflux pump inhibitors of clinically relevant multidrug resistant bacteria

Lamut

Mašič

Kikelj

et al. 2019

Medicinal Research Reviews

146

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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“…It has been a valuable tool for drug discovery [109, 110]. This venture has explored i) the development of preclinical candidates including strategies for lead optimization [111], ii) activity in vivo through the use of alternative scaffolds [112], iii) optimization of potency in the pyridopyrimidine series through the application of a pharmacophore model [113] and iv) extensive structural activity relationships testing toxicity, stability, and solubility [114–117]. Mechanistically, PAβN itself is a MES substrate that acts as a competitive inhibitor [117–120].…”

Section: Rnd-based Epismentioning

confidence: 99%

Microbial Efflux Pump Inhibition: Tactics and Strategies

Tegos

Haynes²,

Strouse³

et al. 2011

CPD

132

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Traditional antimicrobials are increasingly suffering from the emergence of multidrug resistance among pathogenic microorganisms. To overcome these deficiencies, a range of novel approaches to control microbial infections are under investigation as potential alternative treatments. Multidrug efflux is a key target of these efforts. Efflux mechanisms are broadly recognized as major components of resistance to many classes of chemotherapeutic agents as well as antimicrobials. Efflux occurs due to the activity of membrane transporter proteins widely known as Multidrug Efflux Systems (MES). They are implicated in a variety of physiological roles other than efflux and identifying natural substrates and inhibitors is an active and expanding research discipline. One plausible alternative is the combination of conventional antimicrobial agents/antibiotics with small molecules that block MES known as multidrug efflux pump inhibitors (EPIs). An array of approaches in academic and industrial research settings, varying from high-throughput screening (HTS) ventures to bioassay guided purification and determination, have yielded a number of promising EPIs in a series of pathogenic systems. This synergistic discovery platform has been exploited in translational directions beyond the potentiation of conventional antimicrobial treatments. This venture attempts to highlight different tactical elements of this platform, identifying the need for highly informative and comprehensive EPI-discovery strategies. Advances in assay development genomics, proteomics as well as the accumulation of bioactivity and structural information regarding MES facilitates the basis for a new discovery era. This platform is expanding drastically. A combination of chemogenomics and chemoinformatics approaches will integrate data mining with virtual and physical HTS ventures and populate the chemical-biological interface with a plethora of novel chemotypes. This comprehensive step will expedite the preclinical development of lead EPIs.

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MexAB-OprM specific efflux pump inhibitors in Pseudomonas aeruginosa. Part 2: achieving activity in vivo through the use of alternative scaffolds

Cited by 53 publications

References 19 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

Efflux pump inhibitors of clinically relevant multidrug resistant bacteria

Microbial Efflux Pump Inhibition: Tactics and Strategies

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