A Fungal Defensin Inhibiting Bacterial Cell-Wall Biosynthesis with Non-Hemolysis and Serum Stability

Abstract

Defensins are a class of cationic disulfide-bridged antimicrobial peptides (AMPs) present in many eukaryotic organisms and even in bacteria. They primarily include two distinct but evolutionarily related superfamilies (cis and trans). Defensins in fungi belong to the members of the cis-superfamily with the cysteine-stabilized α-helical and β-sheet fold. To date, many fungal defensin-like peptides (fDLPs) have been found through gene mining of the genome resource, but only a few have been experimentally characterized. Here, we report the structural and functional characterization of Pyronesin4 (abbreviated as Py4), a fDLP previously identified by genomic sequencing of the basal filamentous ascomycete Pyronema confluens. Chemically, synthetic Py4 adopts a native-like structure and exhibits activity on an array of Gram-positive bacteria including some clinical isolates of Staphylococcus and Staphylococcus warneri, a conditioned pathogen inhabiting in human skin. Py4 markedly altered the bacterial morphology and caused cytoplasmic accumulation of the cell-wall synthesis precursor through binding to the membrane-bound Lipid II, indicating that it works as an inhibitor of cell-wall biosynthesis. Py4 showed no hemolysis and high mammalian serum stability. This work identified a new fungal defensin with properties relevant to drug exploration. Intramolecular epistasis between mutational sites of fDLPs is also discussed.

Truncated Pleurocidin Derivative with High Pepsin Hydrolysis Resistance to Combat Multidrug-Resistant Pathogens

“…The stability of AMPs is an important prerequisite for their effectiveness in vivo [ 26 , 27 ]. Thus, we evaluated the changes of antibacterial activity of Pleu and its modified peptides at different temperatures (40 to 121 °C) and pH (2 to 12).…”

“…We found that monovalent cations had little effect on the antibacterial activity of peptides, while divalent cations greatly weakened the activity of Pleu and its modified peptides ( Table 3 ). Furthermore, the media containing 10% fetal bovine serum, plasma and DMEM were used to simulate the matrix environment in vivo [ 27 ]. The results showed that these three substances would not weaken the antibacterial activity of the compounds we tested.…”

A case of exudative pleuritis caused by Staphylococcus warneri

“…It is isolated from fermented foods, and has been also been isolated among animals, e.g. in dogs, cats, goats, horses, monkeys, pigs, rodents and sheep, as well as in fish food [2,16,17,18,19,20,21]. In humans, the most common sites of isolation are the skin of the lower limbs, arms, head and nostrils.…”

“…As long ago as 1891, the American pathologist William H. Welch, in his work 'Conditions underlying the infection of wounds', pointed out the obvious fact that bacteria are responsible for wound infection. He also described Staphylococcus epidermidis albus, a coagulase-negative staphylococcus, as a bacterium that almost constantly colonises human skin, but also presented it as a potential pathogen that could be responsible for wound infection [1,2]. With the continuous development of medicine, including the increasing use of invasive techniques, the importance of coagulasenegative staphylococci is increasing significantly [3,4,5,6,7].…”

An Overview of the Potentialities of Antimicrobial Peptides Derived from Natural Sources

“…Eukaryotes and bacteria can produce defensins. Defensins are a class of cysteine-rich AMPs with short, cationic disulfide bridges [ 54 ]. They can be grouped into two superfamilies (cis and trans) ( Figure 4 ).…”