Navigating Antibiotic Resistance in Gram‐Negative Bacteria: Current Challenges and Emerging Therapeutic Strategies

Abstract The rapid rise of antibiotic resistance poses a severe global health crisis, necessitating new approaches to counter this growing threat. The problem is exacerbated in Gram‐negative bacterial pathogens as many antibiotics are unable to enter these cells owing to their unique additional outer membrane barrier. In this review, we discuss the challenges of targeting Gram‐negative bacteria, including the complexity of the outer membrane, as well as the presence of efflux pumps and β‐lactamases that contribute to resistance. We also review solutions proposed to facilitate the entry and accumulation of antibiotics in Gram‐negative bacteria. These involve using existing antibiotics in combination with other inhibitors to attack the bacterial cell synergistically. We also highlight approaches to target Gram‐negative pathogens via novel modes of action, providing new strategies to tackle antibiotic resistance.