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

Abstract

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.

Possible Role of Curcumin as ection an Efflux Pump Inhibitor in Multi Drug Resistant Clinical Isolates of Pseudomonas aeruginosa

“…As long as these inhibitors are extruded outside the cells by the efflux pumps, the concentration of antibiotic increases intracellularly, eventually leading to cell death. Peptidomimetic compounds with phenylalanine arginyl beta naphthylamide (PAβN) also known as MC-207,110 have been used as broad spectrum EPI for Pseudomonas aeruginosa [8,9]. In addition to inhibition of efflux pump activity, PAβN…”

Study on the Role of Efflux Pump in Drug Resistance of Pseudomonas aeruginosa

“…MexA-MexB-OprM, MexC-MexDOprJ, MexE-MexF-OprN and MexXMexY-OprM are common efflux pumps known in P.aeruginosa. 2,9 This study was undertaken to know the role of efflux pump in drug resistance of Pseudomonas aeruginosa. For this, a known efflux pump inhibitor Phenylalanine argynyl β-naphthylamide (PAβN), a broadspectrum synthetic and toxic efflux pump inhibitor was used.…”

“…It is capable of significantly reducing fluoroquinolone resistance in P. aeruginosa. 2 Curcumin is a natural extract derived from rhizomes of the plant Curcuma longa (Zingiberaceae) grown in regions of India and South East Asia. Extensive research in this field has shown its activity as an antiinflammatory, antiviral, antioxidant and anticancer agent.…”

“…The third efflux operon MexEF-oprN confers resistance to quinolones, chloramphenicol and trimethoprim. 2 Use of efflux pump inhibitors improve and potentiate the activity of exported antibiotics.…”

New Structural Templates for Clinically Validated and Novel Targets in Antimicrobial Drug Research and Development

“…The significant progress achieved on this target class contributes to alleviate the upcoming antibiotic crisis in short to medium term. Also several promising efflux pump inhibitors for the AcrAB-TolC and MexAB-OrpM efflux pumps have been discovered (Scheme 9) (Askoura et al 2011;Tegos et al 2011;Opperman and Nguyen 2015;Venter et al 2015), but so far none of them have entered the clinic.…”