Abstract
Owing to the challenges faced by conventional therapeutics, novel peptide antibiotics against multidrug-resistant (MDR) gram-negative bacteria need to be urgently developed. We had previously designed Pro9-3 and Pro9-3D from the defensin of beetle Protaetia brevitarsis; they showed high antimicrobial activity with cytotoxicity. Here, we aimed to develop peptide antibiotics with bacterial cell selectivity and potent antibacterial activity against gram-negative bacteria. We designed 10-meric peptides with increased cationicity by adding Arg to the N-terminus of Pro9-3 (Pro10-1) and its D-enantiomeric alteration (Pro10-1D). Among all tested peptides, the newly designed Pro10-1D showed the strongest antibacterial activity against Escherichia coli, Acinetobacter baumannii, and MDR strains with resistance against protease digestion. Pro10-1D can act as a novel potent peptide antibiotic owing to its outstanding inhibitory activities against bacterial film formation with high bacterial cell selectivity. Dye leakage and scanning electron microscopy revealed that Pro10-1D targets the bacterial membrane. Pro10-1D inhibited inflammation via Toll Like Receptor 4 (TLR4)/Nuclear factor-κB (NF-κB) signaling pathways in lipopolysaccharide (LPS)-stimulated RAW264.7 cells. Furthermore, Pro10-1D ameliorated multiple-organ damage and attenuated systemic infection-associated inflammation in an E. coli K1-induced sepsis mouse model. Overall, our results suggest that Pro10-1D can potentially serve as a novel peptide antibiotic for the treatment of gram-negative sepsis.
Highlights
Overwhelming pathogenic stimuli can lead to the progression of host immune response to systemic inflammatory response syndrome (SIRS), increasing the severity of infections and inducing pathological processes of sepsis
The results revealed that the third 9-meric peptide designed from protaetiamycine 9Pbw3, which was named Pro9-3 in this study, and its enantiomer containing two Trp amino acids (Pro9-3D) exhibited potent antibacterial activities along with toxic effects on mammalian cells [31]
HLF1-11 derived from human lactoferrin is in phase 1 trials [37], and P-113 derived from human histatin-5 [35,38] and Omiganan derived from indolicidin are in phase 3 trials [39]
Summary
Overwhelming pathogenic stimuli can lead to the progression of host immune response to systemic inflammatory response syndrome (SIRS), increasing the severity of infections and inducing pathological processes of sepsis. Sepsis is a multifaceted syndrome caused by an aberrated immune response to bacterial infections, thereby culminating in excessive inflammation, organ dysfunction, and even death [1,2]. Infections by gram-negative bacteria are an urgent problem because the outer cell membrane of bacteria consists of lipopolysaccharide (LPS), which triggers aberrant cascades of the inflammatory response and hinders development of new antibiotics against resistant infections [4,5]. The search for a novel class of antibiotic agents that can combat and overcome resistant events related to sepsis is urgently required
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