From the Guidelines
Efflux pumps are a crucial mechanism of antimicrobial resistance (AMR) in bacteria, particularly in Pseudomonas aeruginosa, where they can confer resistance to multiple drug classes, including piperacillin, ceftazidime, cefepime, and fluoroquinolones 1.
Key Points
- Efflux pumps are protein transport systems that actively expel antibiotics and other toxic compounds from bacterial cells, reducing intracellular drug concentrations to non-lethal levels.
- The most clinically significant efflux systems include the RND (Resistance-Nodulation-Division) family in Gram-negative bacteria, particularly the AcrAB-TolC system in Escherichia coli and Pseudomonas aeruginosa.
- These pumps can confer resistance to multiple drug classes simultaneously, including tetracyclines, fluoroquinolones, macrolides, and certain β-lactams.
- Efflux-mediated resistance is particularly concerning because a single pump can provide protection against structurally diverse antibiotics, contributing to multidrug resistance.
Mechanism of Resistance
- In Pseudomonas aeruginosa, efflux pumps can be expressed all the time or may be upregulated by mutation, leading to resistance to various antimicrobial agents 1.
- The encoding mechanism of bacterial resistance to an antibiotic's effect may be located on mobile genetic elements, such as plasmids or transposons, which can be inherited by future progeny of the bacterium or transferred to other strains of the same species or other species 2.
Clinical Implications
- Clinically, efflux-mediated resistance often works in conjunction with other resistance mechanisms like target site mutations or enzymatic drug inactivation, creating highly resistant pathogens.
- To counter efflux-mediated resistance, combination therapies may be employed, and researchers are developing efflux pump inhibitors (EPIs) that could potentially restore antibiotic susceptibility when administered alongside conventional antibiotics.
- The rise in antimicrobial resistance is of national and international concern, and the use of antibiotics can lead to the disappearance of non-pathogenic commensal bacteria and their replacement by resistant organisms, resulting in "collateral damage" associated with antibiotic use 2.
From the Research
Efflux Pumps and Antibiotic Resistance
- Efflux pumps are proteins located in the bacterial membranes that play a crucial role in antibiotic resistance by expelling antibiotics out of the cell, reducing their effectiveness 3, 4, 5, 6, 7.
- These pumps can contribute to the emergence of high-level antibiotic resistance mechanisms, leading to severe complications during the treatment of infectious diseases 3.
- Efflux pumps can extrude a structurally diverse class of antibiotics, giving rise to multi-drug resistant (MDR) bacteria 4, 6.
Mechanisms of Efflux Pumps
- The resistance-nodulation-division (RND) transporter superfamily is one of the most important determinants of efflux-mediated resistance in gram-negative bacteria 4.
- RND pumps demonstrate broad substrate specificities, facilitating the extrusion of multiple chemical classes of antibiotics from the bacterial cell 4.
- Efflux pumps can be inhibited by efflux pump inhibitors (EPIs), which can restore the activity of antibiotics and limit the emergence of MDR strains 3, 5, 6, 7.
Efflux Pump Inhibitors (EPIs)
- EPIs are molecules that can inhibit efflux pumps, rendering pathogens susceptible to antimicrobial agents 5, 6, 7.
- Several chemical families of EPIs have been described and characterized, and some inhibitor compounds display efficient activity against major efflux pumps 5.
- The use of EPIs can induce a significant reduction of resistance to one or more antibiotics to which the bacteria were initially resistant 5.