Infection with multidrug-resistant (MDR) organisms such as Klebsiella pneumoniae, Pseudomonas aeruginosa, Enterococcus faecium, Escherichia coli (ESKAPEE pathogens), Staphylococcus aureus, Enterobacter spp. and Acinetobacter baumannii, is a major threat to the public health of the world population. However, currently, there are no drugs available that can effectively resist MDR organisms.
Study: Engineered peptide PLG0206 overcomes limitations of a challenging antimicrobial drug class. Image credit: Christoph Burgstedt / Shutterstock.com
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Almost forty years have passed since the discovery of carbapenems. However, despite the effectiveness of these antibiotics, there is still an urgent need for new and effective antimicrobial agents that can effectively combat antibiotic-resistant microorganisms.
Natural antimicrobial peptides (AMPs) have shown intrinsic defense mechanisms against numerous species. The paucity in clinical development of AMPs has been attributed to their toxicity, limited in vivo activity, lack of systemic activity, and suboptimal pharmacokinetic (PK) properties.
A recent PLoS ONE study reports the development of a synthetic antibacterial peptide (PLG0206), previously known as WLBU2. The newly designed PLG0206 is an amino acid peptide consisting of valine, arginine and tryptophan residues, which ensures maximum bacterial membrane binding and interaction and minimal toxicity. Previous research has indicated that PLG0206 is effective against a broad spectrum of pathogens, including the more potent biofilm S. aureus and P. aeruginosa.
About the study
The current study hypothesized that PLG0206 might be effective against infections caused by MDR bacteria. All preclinical evaluations of PLG0206, as well as related in vitro and in vivo evaluations, were also included in the current study. This evidence supported the claim that this antimicrobial compound was an active antibacterial agent, which could overcome the limitations associated with available commercial and experimental antibiotics.
Most traditional antibiotics lose their effectiveness against bacterial biofilms compared to planktonic cells. With this limitation in mind, the present study used a large library of ESKAPEE pathogen clinical isolates to determine whether PLG0206 possessed rapid and broad-spectrum bactericidal activity against Gram-positive and Gram-negative MDR pathogens in both biofilm and growth states. planktonic growth.
The main advantage of PLG0206 is the rational design that allows it to overcome many deficiencies associated with traditional antibiotics and AMPs, including the lack of anti-biofilm activity and pathogen resistance.
Results of the study
In vivo experiments in several animal models revealed that PLG0206 was effective against MDR infection. For example, a large animal model of periprosthetic joint infections (PJI) demonstrated the efficacy of PLG0206 in reducing biofilm-based S. aureus infection. Similar results were obtained in a murine model of uropathogenic urinary tract infection (UTI) by E. coli treated with PLG0206.
Experiments based on animal models also indicated a low toxic profile for systemic and local use of PLG0206. A large rabbit PJI animal model study confirmed the ability of PLG0206 to maintain biofilm-associated activity without apparent toxicity. Notably, all animals showed prolonged survival after a single PLG0206 treatment following S. aureus infection.
A murine model revealed that systemic administration of PLG0206 could more effectively reduce bacterial burdens in both bladder and kidney compared to antibiotic control. In addition, PLG0206 was found to be safe and well tolerated in humans who received the agent intravenously (IV). This clinical study revealed linear PK properties with a mean terminal half-life ranging from 6.5 to 11.2 hours when administered as single IV doses ranging from 0.05 to 1 mg/kg.
Compared to Gram-positive bacteria, Gram-negative bacteria are more likely to develop antibiotic resistance. In spontaneous mutation frequency (SMF) studies, the high MIC values of PLG0206 indicated that Gram-positive pathogens did not produce spontaneous mutants; however, this was not the case for P. aeruginosa.
An optimal concentration of PLG0206 was found to effectively reduce P. aeruginosa colonies, thereby inhibiting the development of spontaneous mutants. Unfortunately, available antimicrobial chemotherapeutic agents are not able to eliminate persistent biofilms. Scientists are currently exploring the mechanism associated with PLG0206’s resistance against P. aeruginosa.
Conclusions
PLG0206 was found to possess rapid and broad-spectrum bactericidal activity against MDR ESKAPEE microbes. Furthermore, this bactericidal agent was found to be effective against biofilm and planktonic growth forms. In vitro and in vivo evaluation of PLG0206 supported its clinical development and underscored the importance of peptides as therapeutic agents.
Journal reference:
- Huang, DB, Brothers, KM, Mandell, JB, et al. (2022) Engineered peptide PLG0206 overcomes limitations of a challenging antimicrobial drug class. PLoS ONE 17(9); e0274815. doi:10.1371/journal.pone.0274815