Structure–Interaction Relationship of Polymyxins with Lung Surfactant

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.