Multidrug-resistant Gram-negative bacteria present an urgent and formidable threat to the global public health.
Polymyxins have emerged as a last-resort
therapy against these 'superbugs'; however, their efficacy against pulmonary
infection is poor. In this study, we integrated chemical biology and molecular dynamics simulations to examine how the alveolar lung
surfactant significantly reduces
polymyxin antibacterial activity. We discovered that lung
surfactant is a
phospholipid-based permeability barrier against
polymyxins, compromising their efficacy against target bacteria. Next, we unraveled the structure-interaction relationship between
polymyxins and lung
surfactant, elucidating the thermodynamics that govern the penetration of
polymyxins through this critical
surfactant layer. Moreover, we developed a novel analog, FADDI-235, which exhibited potent activity against Gram-negative bacteria, both in the presence and absence of lung
surfactant. These findings shed new light on the sequestration mechanism of lung
surfactant on
polymyxins and importantly pave the way for the rational design of new-generation
lipopeptide antibiotics to effectively treat Gram-negative
bacterial pneumonia.