Semisynthetic Guanidino Lipoglycopeptides with Potent In Vitro and In Vivo Antibacterial Activity

Chemistry Infectious Diseases Medicinal Chemistry Life Sciences Medicine Biochemistry Microbiology
antibiotics semisynthetic guanidino lipoglycopeptides antibacterial activity MRSA multidrug-resistant bacteria

Development of Semi-synthetic Guanidino-lipoglycopeptide Antibiotics and Study of Their In Vitro and In Vivo Antibacterial Activities

Background

With the slowdown in antimicrobial drug development and the rapid increase of resistant strains, antibiotic resistance has become a major threat to human health. Particularly, Gram-positive pathogens such as methicillin-resistant Staphylococcus aureus (MRSA) are increasingly causing community and hospital-acquired infections, leading to significant morbidity and mortality. Since its introduction, vancomycin has been widely used to treat infections caused by MRSA and other Gram-positive pathogens. However, in recent years, clinical isolates resistant to vancomycin have emerged, posing new challenges to clinical treatment. These resistant strains include vancomycin-intermediate S. aureus (VISA), heterogeneous VISA (with a resistant subpopulation), and vancomycin-resistant S. aureus (VRSA), all showing varying degrees of resistance to vancomycin. Furthermore, vancomycin-resistant enterococci (VRE) have also become a serious clinical problem, with an estimated 30% of related infections now unresponsive to vancomycin.

Research Objective

This study aims to develop a novel, highly effective semi-synthetic glycopeptide antibiotic to address the current problem of multidrug-resistant Gram-positive pathogen infections. Existing glycopeptide antibiotics such as telavancin, while possessing strong antibacterial activity, are limited in use due to their toxicity and unfavorable pharmacokinetic properties. Therefore, it is particularly important to research and develop a glycopeptide antibiotic that combines high antibacterial activity with good safety.

Paper Source

This paper was completed by a research team including Emma van Groesen, Elma Mons, and others from multiple research institutions such as Leiden University and the University of Bonn. The research findings were published in the journal “Science Translational Medicine” on August 7, 2024.

Research Process

This paper demonstrates the development and testing process of the new antibiotic EVG7 through the following steps: 1. Design and Synthesis Direction: - Introduced guanidino and lipid groups at specific positions of vancomycin using selective reductive amination. - Prepared a series of guanidino glycopeptides containing different fatty tails.

  1. In Vitro Evaluation:

    • Tested the antibacterial activity of these compounds against various Gram-positive strains using the broth microdilution method.
    • Results showed that most compounds had superior antibacterial activity compared to vancomycin.

  2. In Vivo Evaluation:

    • Evaluated the in vivo antibacterial effect of EVG7 in a mouse thigh infection model through subcutaneous or intravenous administration.
    • Results indicated that EVG7’s antibacterial effect was superior to vancomycin even at lower doses.

  3. Toxicity Assessment:

    • Cytotoxicity tests of EVG7 in HepG2 and HEK293 cells showed no cytotoxicity even at high concentrations.
    • EVG7 showed no mutagenicity in the Ames test.
    • In rat repeated-dose toxicity studies, EVG7 demonstrated good tolerability and low nephrotoxicity.

Main Results

  1. Antibacterial Activity:

    • EVG7 showed significant antibacterial activity against various Gram-positive strains, with MIC values significantly lower than vancomycin and comparable to other clinically used glycopeptide antibiotics.
    • EVG7 demonstrated good antibacterial effects in in vivo infection models of MRSA and VISA.

  2. Toxicity and Pharmacokinetics:

    • EVG7 showed low toxicity in in vitro tests and good safety in rats.
    • Pharmacokinetic studies indicated that EVG7 has good in vivo stability and high plasma protein binding.

  3. Mechanism Studies:

    • EVG7 can bind to the bacterial cell wall precursor Lipid II, effectively blocking cell wall synthesis and to some extent overcoming vancomycin resistance.

Conclusions and Significance

This paper reports the development process of guanidino-lipoglycopeptide antibiotics and their significant antibacterial activity and good safety characteristics. These compounds, especially EVG7, show excellent in vitro and in vivo antibacterial activity and good toxicity safety, with potential clinical application value. Next, more advanced in vivo model evaluations will be conducted to further understand their toxicity and pharmacokinetic characteristics and determine their clinical potential in treating severe Gram-positive bacterial infections.

Research Highlights

  1. Novel Antibiotic:

    • Developed semi-synthetic glycopeptides containing guanidino and variable lipid groups, demonstrating highly effective antibacterial activity.

  2. Effective Overcoming of Resistance:

    • EVG7 can bind to Lipid II in vancomycin-resistant strains and showed significant antibacterial effects.

  3. Low Toxicity:

    • EVG7 demonstrated low toxicity in in vivo and in vitro safety studies, particularly excelling in nephrotoxicity studies.

Application Prospects

The guanidino-lipoglycopeptide antibiotics developed in this study have the potential to replace currently widely used but significantly toxic glycopeptide antibiotics in clinical practice, addressing serious infections caused by Gram-positive bacteria, especially in the context of prevalent multidrug-resistant strains. Further clinical studies are needed to confirm their safety and efficacy. This will bring new hope for the development of antimicrobial drugs and the resolution of resistance problems.