MexAB-OprM specific efflux pump inhibitors in Pseudomonas aeruginosa. Part 5: Carbon-substituted analogues at the C-2 position

Yoshida, Kenichi; Nakayama, Kiyoshi; Kuru, Noriko; Kobayashi, Shozo; Ohtsuka, Masaya; Takemura, Makoto; Hoshino, Kazuki; Kanda, Hiroko; Zhang, Jason Z.; Lee, Ving J.; Watkins, William J.

doi:10.1016/j.bmc.2005.10.043

Cited by 44 publications

(17 citation statements)

References 20 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%

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%

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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“…3b) with improved solubility (e.g. morpholine derivative) that showed higher activity through the potentiation of flouroquinolones and β -lactam antibiotics in addition to inhibition of the β -lactam efflux (17, 48, 49). …”

Section: Structure-activity Relationship Of Peptidomimetic Compoundsmentioning

confidence: 99%

Efflux pump inhibitors (EPIs) as new antimicrobial agents against Pseudomonas aeruginosa

Askoura

Mottawea

Abujamel

et al. 2011

Libyan Journal of Medicine

118

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Pseudomonas aeruginosa is an opportunistic human pathogen and one of the leading causes of nosocomial infections worldwide. The difficulty in treatment of pseudomonas infections arises from being multidrug resistant (MDR) and exhibits resistance to most antimicrobial agents due to the expression of different mechanisms overcoming their effects. Of these resistance mechanisms, the active efflux pumps in Pseudomonas aeruginosa that belong to the resistance nodulation division (RND) plays a very important role in extruding the antibiotics outside the bacterial cells providing a protective means against their antibacterial activity. Beside its role against the antimicrobial agents, these pumps can extrude biocides, detergents, and other metabolic inhibitors. It is clear that efflux pumps can be targets for new antimicrobial agents. Peptidomimetic compounds such as phenylalanine arginyl β-naphthylamide (PAβN) have been introduced as efflux pump inhibitors (EPIs); their mechanism of action is through competitive inhibition with antibiotics on the efflux pump resulting in increased intracellular concentration of antibiotic, hence, restoring its antibacterial activity. The advantage of EPIs is the difficulty to develop bacterial resistance against them, but the disadvantage is their toxic property hindering their clinical application. The structure activity relationship of these compounds showed other derivatives from PAβN that are higher in their activity with higher solubility in biological fluids and decreased toxicity level. This raises further questions on how can we compact Pseudomonas infections. Of particular importance, the recent resurgence in the use of older antibiotics such as polymyxins and probably applying stricter control measures in order to prevent their spread in clinical sittings.

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MexAB-OprM specific efflux pump inhibitors in Pseudomonas aeruginosa. Part 5: Carbon-substituted analogues at the C-2 position

Cited by 44 publications

References 20 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

Efflux pump inhibitors (EPIs) as new antimicrobial agents against Pseudomonas aeruginosa

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