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

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.