Novel D-form of hybrid peptide (D-AP19) rapidly kills Acinetobacter baumannii while tolerating proteolytic enzymes

Abstract

Antimicrobial peptides (AMPs) are being developed as potent alternative treatments to conventional antibiotics which are unlikely to induce bacterial resistance. They can be designed and modified to possess several druggable properties. We report herein a novel hybrid peptide of modified aurein (A3) and cathelicidin (P7), or A3P7, by a flipping technique. It exhibited potent antibacterial activity against both Gram-negative and -positive pathogenic bacteria but had moderate hemolytic activity. To reduce the sequence length and toxicity, C-terminal truncation was serially performed and eight truncated derivatives (AP12–AP19) were obtained. They had significantly less hemolytic activity while preserving antibacterial activity. Secondary structures of the candidate peptides in environments simulating bacterial membranes (30 mM SDS and 50% TFE), determined by CD spectroscopy, showed α-helical structures consistent with predicted in silico 3D structural models. Among the peptides, AP19 demonstrated the best combination of broad-spectrum antibacterial activity (including toward Acinetobacter baumannii) and minimal hemolytic and cytotoxic activities. A D-form peptide (D-AP19), in which all L-enantiomers were substituted with the D-enantiomers, maintained antibacterial activity in the presence of pepsin, trypsin, proteinase K and human plasma. Both isomers exhibited potent antibacterial activity against multi-drug (MDR) and extensively-drug resistant (XDR) clinical isolates of A. baumannii comparable to the traditional antibiotic, meropenem. D-AP19 displayed rapid killing via membrane disruption and leakage of intracellular contents. Additionally, it showed a low tendency to induce bacterial resistance. Our work suggested that D-AP19 could be further optimized and developed as a novel compound potentially for fighting against MDR or XDR A. baumannii.

Promising applications of D-amino acids in periprosthetic joint infection

“…However, none of the D-AAs were able to protect against infection in vitro or in a murine model in vivo, and D-AAs may not be suitable antivirulence agents. A recent study by Jariyarattanarach et al 280 reported the creation of a novel hybrid D-AA of modified aurein and cathelicidin, where the structures were substituted with hydrophobic and positively charged Trp and Arg. The hybrid D-AA exhibited potent antibacterial activity against A. baumannii and killing via membrane disruption and leakage of intracellular contents with a low tendency to induce bacterial resistance.…”

An Update on the Therapeutic Potential of Antimicrobial Peptides against Acinetobacter baumannii Infections

“…The final peptide rapidly killed A. baumannii ATCC 19606 (MIC = 7.81 µg/mL) via membrane disruption and showed a low tendency to induce bacterial resistance. It also exhibited potent antibacterial activity against MDR and XDR A. baumannii (MIC = 3.91–15.63) [ 176 ]. BP214 is a cationic amphipathic all-D decapeptide developed from a short cecropin A-melittin hybrid peptide BP100 [ 300 ], which showed excellent activity against colistin-resistant A. baumannii and modest hemolytic properties [ 301 ].…”

Influence of Chirality on the Self-Assembly of Dipeptides and Sensing of Fe3+

“…32 Additionally, D-amino acids containing peptide sequences improve therapeutic effects, antimicrobial activity, and enzymatic stability. 33,34 In 1993, Ghadiri et al described hollow peptide nanotubes using alternating D/L-amino acids. 35 Lorenzi and co-workers showed the crystal structures of dipeptides containing alternating D/L-and L/D-amino acids.…”

“…The inclusion of d -amino acids into peptide sequences offers extensive application in peptide chemistry, medicinal chemistry, biological chemistry, and nanotechnology . Additionally, d -amino acids containing peptide sequences improve therapeutic effects, antimicrobial activity, and enzymatic stability. , In 1993, Ghadiri et al described hollow peptide nanotubes using alternating d / l -amino acids . Lorenzi and co-workers showed the crystal structures of dipeptides containing alternating d / l- and l / d- amino acids .…”