Multidrug-resistant Gram-negative bacteria are a serious global threat to human health.
Polymyxins are increasingly used in patients as a last-line
therapy to treat
infections caused by these life-threatening 'superbugs'. Unfortunately,
polymyxin-induced nephrotoxicity is the major dose-limiting factor and understanding its mechanism is crucial for the development of novel, safer
polymyxins. Here, we undertook the first all-atom molecular dynamics simulations of the interaction between four naturally occurring
polymyxins A1, B1, M1 and
colistin A (representative structural variations of the
polymyxin core structure) and the membrane of human kidney proximal tubular cells. All
polymyxins inserted spontaneously into the hydrophobic region of the membrane where they were retained, although their insertion abilities varied.
Polymyxin A1 completely penetrated into the hydrophobic region of the membrane with a unique folded conformation, whereas the other three
polymyxins only inserted their fatty acyl tails into this region. Furthermore, local membrane defects and increased water penetration were induced by each
polymyxin, which may represent the initial stage of cellular membrane damage. Finally, the structure-interaction relationship of
polymyxins was investigated based on atomic interactions at the cell membrane level. The hydrophobicity at positions 6/7 and stereochemistry at position 3 regulated the interactions of
polymyxins with the cell membrane. Collectively, our results provide new mechanistic insights into
polymyxin-induced nephrotoxicity at the atomic level and will facilitate the development of new-generation
polymyxins.