Efflux systems driving resistance and virulence across biological domains

Efflux pumps (EPs) are key contributors to multidrug resistance (MDR) in bacteria, fungi, and cancer cells. These membrane proteins actively extrude a variety of therapeutic agents, reducing their intracellular concentration and thus compromising the efficacy of treatment. Beyond resistance, EPs are also involved in virulence, biofilm formation, immune evasion, and environmental persistence.

This review aimed to provide a comprehensive and critical synthesis of the role of efflux pumps in antimicrobial and antitumoral resistance, as well as their contribution to virulence and persistence across biological domains.

A narrative review was conducted following a structured search strategy in PubMed, Scopus, and Web of Science using combinations of terms related to efflux systems, efflux pumps, resistance mechanisms, virulence factors, detection methods, and inhibitors. The review integrates data from in vitro, in silico, and clinical studies, including both classical detection strategies and emerging technologies such as clustered regularly interspaced short palindromic repeats (CRISPR)-based modulation, biosensors, and microfluidics.

Efflux pumps from different families (e.g., resistance-nodulation-division (RND), ATP-binding cassette (ABC), major facilitator superfamily (MFS)) are implicated in the active extrusion of antimicrobial agents, facilitating MDR and treatment failure in pathogens such as E. coli, P. aeruginosa, M. tuberculosis, Candida albicans, and cancer cells. EPs also regulate biofilm formation, virulence factor secretion, and metabolic adaptation. Classical methods for detecting efflux (e.g., minimum inhibitory concentration (MIC) shifts with inhibitors, fluorometric assays) have technical limitations, while novel technologies offer improved precision. Several natural and synthetic efflux pump inhibitors (EPIs) have demonstrated efficacy in preclinical studies, yet few have progressed to clinical use due to toxicity and pharmacokinetic barriers. CRISPR interference systems and combinatory therapies represent promising advances in overcoming EP-mediated resistance.

Efflux systems are central players in both drug resistance and pathogenicity. Although the development of effective EIs remains challenging, advances in molecular detection, gene editing, and drug design hold potential for translational breakthroughs. A deeper understanding of efflux dynamics across organisms is essential to develop adjuvant therapies and reduce the clinical impact of MDR.