Engineered Cationic Antimicrobial Peptides To Overcome Multidrug Resistance by ESKAPE Pathogens

ABSTRACTMultidrug resistance constitutes a threat to the medical achievements of the last 50 years. In this study, we demonstrated the abilities of twode novoengineered cationic antibiotic peptides (eCAPs), WLBU2 and WR12, to overcome resistance from 142 clinical isolates representing the most common multidrug-resistant (MDR) pathogens and to display a lower propensity to select for resistant bacteriain vitrocompared to that with colistin and LL37. The results warrant an exploration of eCAPs for use in clinical settings.

Rationale-Based,De NovoDesign of Dehydrophenylalanine-Containing Antibiotic Peptides and Systematic Modification in Sequence for Enhanced Potency

ABSTRACTIncreased microbial drug resistance has generated a global requirement for new anti-infective agents. As part of an effort to develop new, low-molecular-mass peptide antibiotics, we used a rationale-based minimalist approach to design short, nonhemolytic, potent, and broad-spectrum antibiotic peptides with increased serum stability. These peptides were designed to attain an amphipathic structure in helical conformations. VS1 was used as the lead compound, and its properties were compared with three series of derivates obtained by (i) N-terminal amino acid addition, (ii) systematic Trp substitution, and (iii) peptide dendrimerization. The Trp substitution approach underlined the optimized sequence of VS2 in terms of potency, faster membrane permeation, and cost-effectiveness. VS2 (a variant of VS1 with two Trp substitutions) was found to exhibit good antimicrobial activity against both the Gram-negativeEscherichia coliand the Gram-positive bacteriumStaphylococcus aureus. It was also found to have noncytolytic activity and the ability to permeate and depolarize the bacterial membrane. Lysis of the bacterial cell wall and inner membrane by the peptide was confirmed by transmission electron microscopy. A combination of small size, the presence of unnatural amino acids, high antimicrobial activity, insignificant hemolysis, and proteolytic resistance provides fundamental information for thede novodesign of an antimicrobial peptide useful for the management of infectious disease.