Abstract
Infections caused by drug-resistant “superbugs” pose an urgent public health threat due to the lack of effective drugs; however, certain mammalian proteins with intrinsic antibacterial activity might be underappreciated. Here, we reveal an antibacterial property against Gram-negative bacteria for factors VII, IX and X, three proteins with well-established roles in initiation of the coagulation cascade. These factors exert antibacterial function via their light chains (LCs). Unlike many antibacterial agents that target cell metabolism or the cytoplasmic membrane, the LCs act by hydrolyzing the major components of bacterial outer membrane, lipopolysaccharides, which are crucial for the survival of Gram-negative bacteria. The LC of factor VII exhibits in vitro efficacy towards all Gram-negative bacteria tested, including extensively drug-resistant (XDR) pathogens, at nanomolar concentrations. It is also highly effective in combating XDR Pseudomonas aeruginosa and Acinetobacter baumannii infections in vivo. Through decoding a unique mechanism whereby factors VII, IX and X behave as antimicrobial proteins, this study advances our understanding of the coagulation system in host defense, and suggests that these factors may participate in the pathogenesis of coagulation disorder-related diseases such as sepsis via their dual functions in blood coagulation and resistance to infection. Furthermore, this study may offer new strategies for combating Gram-negative “superbugs”.
Highlights
Factor VII (FVII), factor IX (FIX), factor X (FX) and their light chains (LCs) exert antibacterial effects In this study, the LCs of FVII, FIX and FX were produced by E. coli BL21 (DE3), and their intact forms, as well as the heavy chain (HC) of FVII, were produced by CHO-DG44 cells
The LCs of FVII, FIX and FX, which share an analogous domain structure,[9,10] are conserved at the amino acid level (Supplementary information, Fig. S1a); equivalent levels of antibacterial activity were identified in the LC of FIX, the LC of FX, as well as the intact FIX and FX (Fig. 1e–h)
These results indicated that the LCs derived from the coagulation factors are critical for the antibacterial activity
Summary
Bacterial pathogens pose one of the most urgent global health threats as a result of their growing resistance to current antibacterial drugs.[1,2] Compared to the Gram-positive bacteria, the Gram-negative bacteria are harder to kill because of the presence of the outer membrane, which contributes to the reduced cell permeability and serves as a mechanism for the antibiotic resistance.[3,4] Bacterial infections, especially those caused by the Gram-negative pathogens, have aroused wide concern due to the lack of effective antimicrobial reagents.[4,5,6] Recently, the World Health Organization (WHO) listed 12 bacteria that pose the greatest threat to human health because of their resistance to antibiotics; among them, three carbapenem-resistant Gramnegative bacteria, Acinetobacter baumannii, Pseudomonas aeruginosa and Enterobacteriaceae, are considered to be of critical priority.[7]. Certain natural mammalian proteins that possess an intrinsic antibacterial property might be underappreciated
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