Abstract
Mammalian cathelicidins act as the potent microbicidal molecules for controlling bacterial infection, and are considered promising alternatives to traditional antibiotics. Their ability to modulate host immune responses, as well as their bactericidal activities, is essential for therapeutic interventions. In this study, we compared the bactericidal activities, antibiofilm activities and immune-modulatory properties of cathelicidins BMAP-27, BMAP-34, mCRAMP, and LL-37, and evaluated the therapeutic efficacy of the combination of BMAP-27 and LL-37 using a mouse pulmonary infection model. Our results showed that all of the four cathelicidins effectively killed bacteria via rapid induction of membrane permeabilization, and BMAP-27 exhibited the most excellent bactericidal activity against diverse bacterial pathogens. BMAP-27, mCRAMP, and LL-37 effectively inhibited biofilm formation, while BMAP-34, mCRAMP and LL-37 exerted immunomodulatory functions with varying degrees of efficacy by stimulating the chemotaxis of neutrophils, inducing the production of reactive oxygen species, and facilitating the formation of neutrophil extracellular traps. Of note, the combination of BMAP-27 and LL-37 effectively enhanced the clearance of Pseudomonas aeruginosa and reduced the organ injury in vivo. Together, these findings highlight that identifying the appropriate synergistic combination of mammalian cathelicidins with different beneficial properties may be an effective strategy against bacterial infection.
Highlights
Overuse of antibiotics in humans and animals contributes to worldwide spread of multidrug-resistant (MDR) strains, such as so-called ESKAPE (Enterococcus faecium, Staphylococcus aureus, Klebsiella pneumoniae, Acinetobacter baumannii, Pseudomonas aeruginosa, and Enterobacter species) pathogens [1]
BMAP-27 adopts the typical amphipathic α-helical structure, with hydrophobic and positively charged residues distributed on each side, while those of BMAP-34, mCRAMP, and LL-37 are more dispersed (Figure 1A,B)
The results showed that all of the four cathelicidins exerted efficient and broad-spectrum activities against Gram-negative and Gram-positive bacteria (Figure 2)
Summary
Overuse of antibiotics in humans and animals contributes to worldwide spread of multidrug-resistant (MDR) strains, such as so-called ESKAPE (Enterococcus faecium, Staphylococcus aureus, Klebsiella pneumoniae, Acinetobacter baumannii, Pseudomonas aeruginosa, and Enterobacter species) pathogens [1]. Mammalian cathelicidins constitute an important family of antimicrobial peptides (AMPs) and are essential defense molecules against microbial infections [3]. They are synthesized as inactive precursors, including a highly conserved N-terminal region known as the cathelin domain, and a C-terminal domain with a varied sequence and length [4]. The immune-modulatory properties remain not well understood, bovine cathelicidin peptides BMAP-27 and BMAP-34 have been shown to efficiently inhibit the growth of pathogenic bacteria [10]. Mammalian cathelicidins are highlighted as promising alternatives to traditional antibiotics for the treatment of bacterial infection [3]
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