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Gram-negative bacterial pathogens are a diverse group of bacteria characterized by a complex cell envelope consisting of an inner cytoplasmic membrane, a thin peptidoglycan cell wall, and a unique outer membrane containing lipopolysaccharides (LPS) (Silhavy et al., 2010, Cold Spring Harb Perspect Biol). This outer membrane acts as a selective permeability barrier that contributes to intrinsic resistance against many antibiotics, making these organisms a primary focus of drug development (WHO, 2024). Key pathogens in this group include Escherichia coli, Pseudomonas aeruginosa, and Klebsiella pneumoniae, which are responsible for a wide range of clinical conditions such as sepsis, pneumonia, and urinary tract infections (CDC, 2019). The clinical management of these infections is increasingly challenged by the emergence of multi-drug resistant (MDR) and extensively drug-resistant (XDR) strains, particularly carbapenem-resistant Enterobacteriaceae (CRE). Current therapeutic interventions target various essential bacterial components, including the cell wall, ribosomes, and nucleic acid synthesis machinery. Developing novel agents that can bypass or inhibit the efflux pumps and low-permeability barriers of Gram-negative bacteria remains a critical priority in infectious disease research.
Inhibition of peptidoglycan synthesis (beta-lactams), disruption of the outer membrane (polymyxins), inhibition of the 30S/50S ribosomal subunits (aminoglycosides, tetracyclines), and inhibition of DNA gyrase/topoisomerase IV (fluoroquinolones).
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