Unseen Enemy: Mechanisms of Multidrug Antimicrobial Resistance in Gram-Negative ESKAPE Pathogens

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Abstract
Multidrug antimicrobial resistance (AMR) represents a formidable challenge in the therapy of infectious diseases, triggered by the particularly concerning gram-negative Enterococcus faecium, Staphylococcus aureus, Klebsiella pneumoniae, Acinetobacter baumannii, Pseudomonas aeruginosa, and Enterobacter spp. (ESKAPE) pathogens. Designated as a “priority” in 2017, these bacteria continue to pose a significant threat in 2024, particularly during the worldwide SARS-CoV-2 pandemic, where coinfections with ESKAPE members contributed to worsened patient outcomes. The declining effectiveness of current treatments against these pathogens has led to an increased disease burden and an increase in mortality rates globally. This review explores the sophisticated mechanisms driving AMR in gram-negative ESKAPE bacteria, focusing on Acinetobacter baumannii, Klebsiella pneumoniae, Pseudomonas aeruginosa, and Enterobacter spp. Key bacterial mechanisms contributing to resistance include limitations in drug uptake, production of antibiotic-degrading enzymes, alterations in drug target sites, and enhanced drug efflux systems. Comprehending these pathways is vital for formulating innovative therapeutic strategies and tackling the ongoing threat posed by these resistant pathogens.

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