Efflux Pump Inhibitors Derived From Natural Sources as Novel Antibacterial Agents Against Pseudomonas aeruginosa: A Review

Abstract

Introduction Pseudomonas aeruginosa is a gram-negative bacterium that can survive in different environments, including soil, plants, and animals. Moreover, it is the most opportunistic human pathogen, particularly in immunocompromised patients, and has been recognized as one of the five main pathogens in nosocomial infections. 1 Pseudomonas diseases are mainly seen in urinary tract infections (UTIs), burn wounds, and pulmonary infections such as cystic fibrosis (CF). Mortality rates in P. aeruginosa infections are up to 50% and 70% in patients with bacteremia and nosocomial pneumonia, respectively. 2 P. aeruginosa infections are diverse, because they have a multiplicity of resistance mechanisms and have developed different metabolic and nutritional pathways. 3 Of the resistance mechanisms to be noted is the formation of biofilms, which provide better protection against different antibiotics and body defense systems. 3 Additionally, low outer cell membrane permeability causes intrinsic resistance to antibiotics and increases the number of multi-drug resistance (MDR) strains in P. aeruginosa (resistance ≥3 antibiotic classes). 4-7 Moreover, the high expression of efflux pumps can rapidly expand antibiotic resistance as well. 8 This review discusses types of efflux pumps, the efflux pumps role in pathogenicity, the importance of efflux pump inhibitors (EPIs), diagnostic methods for their detection, and compounds derived from natural sources that reduce infections caused by MDR P. aeruginosa. Efflux Pumps and Their Importance in Antibiotic Resistance Since the discovery of bacterial efflux pumps in the 1980s, many of them have been characterized. 9 Efflux pumps are membrane proteins and participate in the extrusion of antibiotics and chemicals such as organic solvents, dyes, detergents, intermediate molecules in cellular communications, metabolic products, and biocides in prokaryote and eukaryote cells. 10 Substrates of note of the efflux pumps are oxazolidinones

Effect the Natural Efflux Pump Inhibitor (Berberine) in Multidrug Resistant Kleibsiella pneumoniae Isolated from Urinary Tract Infections in Several Baghdad Hospitals

“…Natural isoquinoline alkaloid berberine (BEB) is found in many different medicinal plants and has been shown to have antibacterial and antifungal actions both on its own and in combination with other medications (25) . Berberine has a synergistic effect by enhancing the bacterial inhibition of some antibiotics (26) .…”

In vitro inhibition of multi-drug resistant Pseudomonas efflux pump by Xylopia aethiopica (Dunal) A. Rich

“…This implies that ISSN: 2789-3928 the fractions potentiated the activity of ciprofloxacin by a mechanism suggestive of inhibition of efflux pump. Efflux pump inhibitors including those from plant extracts may not have independent antimicrobial properties, but when they are used in combination with standard antibiotics, they suppress microbial efflux pump and as well enhance the efficacy of drugs [24].…”

Types and Mechanisms of Efflux Pump Systems and the Potential of Efflux Pump Inhibitors in the Restoration of Antimicrobial Susceptibility, with a Special Reference to Acinetobacter baumannii

“…This has been shown in studies with P. aeruginosa and phage OMKO1 and in studies with E. coli and phages U136B and 132 [ 21 ]. In the study with P. aeruginosa and phage OMKO1, the phage bound the OMP OprM, which is a component of the MexXY and MexAB efflux pumps [ 152 ]. This binding causes the bacteria to modify OprM, which leads to inhibition of the efflux pumps and increases P. aeruginosa susceptibility to tetracycline and erythromycin, which are substrates for the MexXY and MexAB efflux pumps [ 152 ].…”

“…In the study with P. aeruginosa and phage OMKO1, the phage bound the OMP OprM, which is a component of the MexXY and MexAB efflux pumps [ 152 ]. This binding causes the bacteria to modify OprM, which leads to inhibition of the efflux pumps and increases P. aeruginosa susceptibility to tetracycline and erythromycin, which are substrates for the MexXY and MexAB efflux pumps [ 152 ]. In addition, there appears to be a genetic trade off with the use of phages to treat bacterial infections [ 152 , 153 ].…”

“…This binding causes the bacteria to modify OprM, which leads to inhibition of the efflux pumps and increases P. aeruginosa susceptibility to tetracycline and erythromycin, which are substrates for the MexXY and MexAB efflux pumps [ 152 ]. In addition, there appears to be a genetic trade off with the use of phages to treat bacterial infections [ 152 , 153 ]. The bacteria may become more susceptible to antibiotics again as they develop resistance against the phages being used as a treatment.…”