New engineered peptides can prevent the superbug crisis


Infection with multidrug-resistant organisms, such as Klebsiella pneumoniaeAnd the Pseudomonas aeruginosaAnd the Enterococcus faecalis, Escherichia coli (ESKAPEE pathogens), Staphylococcus aureusAnd the Intestinal spp. And the stagnant bomanian, is a major threat to the public health of the world’s population. However, at present, there are no drugs available that can effectively combat multidrug-resistant organisms.

Study: The engineered peptide PLG0206 overcomes the limitations of a challenging antimicrobial drug class.  Image Credit: Christoph Burgstedt / Shutterstock.com

Stady: The engineered peptide PLG0206 overcomes the limitations of the challenging antimicrobial drug class. Image Credit: Christoph Burgstedt / Shutterstock.com

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It has been nearly forty years since the discovery of carbapenems. However, although effectiveness With these antibiotics, there is still an urgent need for new and effective antimicrobial agents that can effectively combat antibiotic-resistant microorganisms.

Naturally occurring antimicrobial peptides (AMP) have demonstrated intrinsic defense mechanisms against many species. The rarity in the clinical development of AMPs has been attributed to their limited toxicity in vivo Activity, lack of systemic activity, and suboptimal pharmacokinetic properties (PK).

newly PLUS ONE The 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 residues of valine, arginine and tryptophan, ensuring maximum binding and interaction of the bacterial membrane and minimal toxicity. Previous research has indicated that PLG0206 is effective against a wide range of pathogens, including the most potent ones s. aureus biofilm and s. aeruginosa.

about studying

The current study hypothesized that PLG0206 could be effective against infection caused by MDR bacteria. All preclinical evaluations of PLG0206, as well as associated in the laboratory And the in vivo evaluations, as they were 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 conventional antibiotics lose their effectiveness against bacterial biofilms compared to planktonic cells. Given this limitation, the current study used a large clinical isolation library of ESKAPEE pathogens to determine whether PLG0206 possesses rapid, broad-spectrum and bactericidal activity against Gram-positive and Gram-negative MDR pathogens in both biofilm and planktonic growth conditions.

The primary advantage of PLG0206 is the rational design that enables it to overcome many shortcomings associated with conventional antibiotics and persistent organic antioxidants, including lack of anti-biofilm activity and pathogenic resistance.

Results

in vivo Experiments using different animal models showed that PLG0206 was effective against MDR infection. For example, a large animal model of periarticular joint infection (PJI) showed the efficacy of PLG0206 in reducing s. aureus infection. Similar results were obtained in a rat model of urinary tract disease e. coli Urinary tract infection (TUI) treated with PLG0206.

Animal model-based experiments also indicated a low level of toxicity for systemic and local use of PLG0206. A large animal model study of the PJI rabbit confirmed the ability of PLG0206 to maintain biomembrane-bound activity with no apparent toxicity. Notably, all animals showed a prolonged survival after a single treatment with PLG0206 thereafter s. aureus infection.

The rat model revealed that systemic administration of PLG0206 could more effectively reduce bacterial loads in both the bladder and kidneys 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 the characteristics of linear PK with a mean half-life of 6.5 to 11.2 hours when administered as single intravenous doses of 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, elevated PLG0206 MIC values ​​indicated that Gram-positive pathogens do not produce spontaneous mutations; However, this was not the case with s. aeruginosa.

It was found that the optimal concentration of PLG0206 decreases P. aeruginosa colonies effectively, thus inhibiting the development of spontaneous mutations. Unfortunately, the available antimicrobial chemotherapeutic agents are not able to eradicate persistent biofilms. Currently, scientists are exploring the mechanism associated with the resistance of PLG0206 against s. aeruginosa;

Conclusions

It was found that PLG0206 possesses broad-spectrum and rapid bactericidal activity against ESKAPEE MDR microbes. Moreover, this bactericidal agent was found to be effective against both biofilm and plankton growth forms. in the laboratory And the in vivo The evaluation of PLG0206 supported its clinical development and emphasized the importance of peptides as therapeutic agents.

Journal reference:

  • Huang, DB, Brothers, KM, Mandel, JB, et al. (2022) The PLG0206 engineered peptide overcomes the limitations of a challenging antimicrobial class. PLUS ONE 17(9); e0274815. doi: 10.1371/journal.pone.0274815



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