Infections with multidrug-resistant (MDR) organisms such as Klebsiella pneumoniae, Pseudomonas aeruginosa, Enterococcus faecium, Escherichia coli (ESKAPEE pathogens), Staphylococcus aureus, Enterobacter spp., a Acinetobacter baumannii, is a significant public health threat to the global population. However, there are currently no drugs available that effectively resist MDR organisms.
Studies: The engineered peptide PLG0206 overcomes the limitations of a challenging class of antimicrobial drugs. Image credit: Christoph Burgstedt / Shutterstock.com
Almost forty years have passed since the discovery of carbapenems. However, despite the effectiveness of these antibiotics, there remains an urgent need for new and effective antimicrobial agents that can effectively combat antibiotic-resistant microorganisms.
Naturally occurring antimicrobial peptides (AMPs) exhibit intrinsic defense mechanisms against many species. The lack of clinical development of AMPs has been attributed to their limited toxicity in vivo activity, lack of systemic activity, and suboptimal pharmacokinetic (PK) properties.
Recent PLoS ONE study reports the development of a synthetic antibacterial peptide (PLG0206), formerly known as WLBU2. The newly designed PLG0206 is an amino acid peptide consisting of valine, arginine and tryptophan residues, ensuring maximum bacterial membrane binding and interaction and minimal toxicity. Previous research has shown that PLG0206 is effective against a wide range of pathogens, including the most potent WITH. aureus biofilm a P. aeruginosa.
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 evaluation, were also included in the current study. This evidence supported the claim that this antimicrobial compound was an active antibacterial agent that 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, this study utilized ESKAPEE’s extensive library of clinical pathogen isolates to determine whether PLG0206 has rapid, broad-spectrum bactericidal activity against both Gram-positive and Gram-negative MDR pathogens in both biofilm and planktonic states.
The primary advantage of PLG0206 is its rational design, which allows it to overcome many of the shortcomings associated with traditional antibiotics and AMPs, including insufficient antibiofilm activity and pathogen resistance.
In vivo experiments using various 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. WITH. aureus infection. Similar results were obtained in a mouse model of uropathogenicity E. coli urinary tract infection (TUI) treated with PLG0206.
Animal model experiments also showed a low toxic profile for systemic and topical use of PLG0206. A large rabbit study in an animal model of PJI confirmed the ability of PLG0206 to maintain biofilm-associated activity without apparent toxicity. Notably, all animals showed prolonged survival after a single PLG0206 treatment thereafter WITH. aureus infection.
A mouse model revealed that systemic administration of PLG0206 could more effectively reduce bacterial burden in both bladders and kidneys compared to an antibiotic control. Additionally, PLG0206 was found to be safe and well tolerated in people who received the agent intravenously (IV). This clinical study revealed linear pharmacokinetic properties with a median terminal half-life ranging between 6.5 and 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 resistance to antibiotics. In spontaneous mutation frequency (SMF) studies, elevated MICs of PLG0206 indicated that Gram-positive pathogens did not produce spontaneous mutants; however, this was not the case with P. aeruginosa.
The optimal concentration of PLG0206 was found to decrease P. aeruginosa effectively inhibit the development of spontaneous mutants. Unfortunately, available antimicrobial chemotherapeutic agents are unable to eliminate persistent biofilms. Currently, researchers are investigating the mechanism associated with PLG0206’s resistance against P. aeruginosa.
PLG0206 was found to have broad-spectrum and rapid bactericidal activity against ESKAPEE MDR microbes. Furthermore, this bactericidal agent was found to be effective against both 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.
Link to journal:
- 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
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