Abstract
<jats:p>The escalation of antimicrobial resistance (AMR) among Gram-negative pathogens constitutes one of the most severe threats facing modern clinical medicine, with recent global burden analyses attributing over a million deaths annually to resistant bacterial infection. Conventional antibiotic discovery remains constrained by mutable intracellular targets, inducible efflux systems, and enzymatic drug degradation. This paper advances a purely theoretical, non-experimental biochemical hypothesis centered on the thermodynamic destabilisation of the Gram-negative outer membrane by arresting the lipopolysaccharide (LPS) transport machinery — the seven-protein LptA–G transenvelope bridge responsible for maintaining the membrane's essential lipid asymmetry. Using standard Gibbs free energy relationships, we propose a binding-energy threshold framework by which a hypothetical small-molecule ligand could immobilize the periplasmic LptA oligomer, arresting the membrane-to-membrane protein bridge shown experimentally to transport LPS in a "PEZ-dispenser" fashion. Because this hydrophobic transport channel is structurally conserved across resistant pathogen families independent of their surface-level resistance mutations, we argue it represents a mechanistically universal chokepoint. The paper situates this hypothesis within known thermodynamic and structural literature, proposes falsifiable experimental protocols, and critically examines the pharmacokinetic barriers — principally solubility and off-target toxicity — that separate theoretical elegance from clinical translation.</jats:p>