Infection with multidrug-resistant (MDR) organisms, similar to Klebsiella pneumoniae, Pseudomonas aeruginosa, Enterococcus faecium, Escherichia coli (ESKAPEE pathogens), Staphylococcus aureus, Enterobacter spp., and Acinetobacter baumannii, is a major public health threat to the worldwide population. Nonetheless, at present, no drugs can be found that may effectively resist MDR organisms.

Study: Engineered peptide PLG0206 overcomes limitations of a difficult antimicrobial drug class. Image Credit: Christoph Burgstedt / Shutterstock.com

Background

Almost forty years have passed because the discovery of carbapenems. Yet, despite the efficacy of those antibiotics, there stays an urgent need for brand spanking new and effective antimicrobial agents that may effectively combat antibiotic-resistant microorganisms.

Naturally occurring antimicrobial peptides (AMP) have exhibited intrinsic defense mechanisms against quite a few species. The scarcity within the 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 event of an artificial antibacterial peptide (PLG0206), previously often 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 minimum toxicity. Prior research has indicated that PLG0206 is effective against a broad spectrum of pathogens, including probably the most potent S. aureus biofilm and P. aeruginosa.

Concerning the study

The present study hypothesized that PLG0206 may very well be effective against infections brought on by MDR bacteria. All preclinical evaluations of PLG0206, in addition to the related in vitro and in vivo assessments, were also included in the present study. This evidence supported the claim that this antimicrobial compound was an energetic antibacterial agent, which could overcome limitations related to the available business and experimental antibiotics.

Most traditional antibiotics lose their efficacy against bacterial biofilms in comparison with planktonic cells. Considering this limitation, the current study utilized a sizeable clinical isolate library of ESKAPEE pathogens to find out if PLG0206 possessed rapid, broad-spectrum, bactericidal activity against each Gram positive and Gram negative MDR pathogens in each biofilm and planktonic growth states. 

The first advantage of PLG0206 is the rational design that permits it to beat many shortfalls related to traditional antibiotics and AMPs, including a scarcity of anti-biofilm activity and pathogenic resistance.

Study findings

In vivo experiments using various animal models revealed that PLG0206 was effective against MDR infection. For instance, a big animal model of periprosthetic joint infections (PJI) demonstrated the effectiveness of PLG0206 in reducing biofilm-based S. aureus infection. Similar results were obtained in a murine model of uropathogenic E. coli urinary tract infection (TUI) treated with PLG0206.

Animal model-based experiments also indicated a low toxic profile for systemic and native use of PLG0206. A big rabbit PJI animal model study confirmed the flexibility of PLG0206 to take care of biofilm-associated activity with no apparent toxicity. Notably, all animals exhibited prolonged survival after a single treatment with PLG0206 after S. aureus infection.

A murine model revealed systematic administration of PLG0206 could more effectively reduce bacterial loads in each bladders and kidneys as in comparison with the antibiotic control. As well as, PLG0206 was found to be secure and well tolerated in humans who received the agent intravenously (IV). This clinical study revealed linear PK properties with a median terminal half-life that ranged between 6.5 and 11.2 hours when administered as single IV doses starting from 0.05 to 1 mg/kg.

In comparison with Gram-positive bacteria, Gram-negative bacteria usually tend to develop antibiotic resistance. In spontaneous mutation frequency (SMF) studies, elevated PLG0206 MIC values indicated that Gram-positive pathogens didn’t produce spontaneous mutants; nonetheless, this was not the case with P. aeruginosa. 

An optimal concentration of PLG0206 was found to cut back P. aeruginosa colonies effectively, thus inhibiting the event of spontaneous mutants. Unfortunately, available antimicrobial chemotherapeutic agents usually are not capable of eliminate persistent biofilms. Currently, scientists are exploring the mechanism related to PLG0206 resistance against P. aeruginosa. 

Conclusions

PLG0206 was found to own broad-spectrum and rapid bactericidal activity against ESKAPEE MDR microbes. Moreover, this bactericidal agent was found to be effective against each biofilm and planktonic growth forms. In vitro and in vivo assessment of PLG0206 supported its clinical development and underscored the importance of peptides as therapeutic agents.

Journal reference:

• Huang, D. B., Brothers, K. M., Mandell, J. B., et al. (2022) Engineered peptide PLG0206 overcomes limitations of a difficult antimicrobial drug class. PLoS ONE 17(9); e0274815. doi:10.1371/journal.pone.0274815