A novel antibiotic-host defense peptide conjugate with multiple talents

March 31, 2022

Andy An Photo - Hancock Lab

Sarah Bowers

 

Written by: Sarah Bowers, PhD Student, Brown Lab (left)
Edited by: Andy An, MD/PhD Student, Hancock Lab (right)

In a world that continues to be rattled by the coronavirus pandemic, another global health crisis is progressing. A recent study estimates that 1.27 million deaths were caused worldwide by bacterial antimicrobial resistance in 2019 1. Current therapeutic approaches based on antibiotics are under severe threat due to the increasing prevalence of antibiotic resistant bacteria, rendering existing therapies ineffective. Furthermore, physicians are limited by a lack of specific therapies for difficult to treat bacterial populations, including biofilm-forming bacteria that account for 65-85% of all microbial infections in humans 2,3. As such, identifying effective, anti-infective therapies remains a priority that some experts argue should not be overlooked in the era of COVID-19 1,2.

Figure 1. Schematic illustrating the multimodal activity of the novel vancomycin-innate defence regulator conjugate, V-IDR1018. The conjugate was found to have (a) antimicrobial, (b) antibiofilm, and (c) immunomodulatory activities. Figure from Etayash et al. (2021) [reference 4 in text].

Figure 1. Schematic illustrating the multimodal activity of the novel vancomycin-innate defence regulator conjugate, V-IDR1018. The conjugate was found to have (a) antimicrobial, (b) antibiofilm, and (c) immunomodulatory activities. Figure from Etayash et al. (2021) [reference 4 in text].

In a recent study by the Hancock Lab, Etayash and colleagues identified a novel vancomycin-innate defence regulator conjugate (V-IDR1018) as a promising candidate for the treatment of bacterial infections 4. This strategy involved conjugation of the immunomodulatory host defense peptide IDR1018 to an existing antibiotic, vancomycin. Whereas vancomycin alone works against Gram-positive bacteria, such as methicillin-resistant S. aureus (MRSA), IDR1018 is a synthetic peptide with recognized immunomodulatory and antibiofilm activities. By combining these entities, the authors aimed to create a compound with enhanced biological function.

Strikingly, the conjugate constructed by the Hancock Lab, termed “V-IDR1018”, was found to be multi-talented. V-IDR1018 could not only kill bacteria, but also eradicate biofilms and modulate the activity of innate immune cells (Figure 1).

To evaluate antimicrobial activity in vitro, the authors tested the minimal inhibitory concentration (MIC) of V-IDR1018 against representative strains of Gram-positive pathogens. The activity of the conjugate was increased by four-fold compared to the peptide alone. Furthermore, based on minimal biofilm eradication concentration (MBEC), V-IDR1018 showed an antibiofilm activity more than 16-fold greater than that of vancomycin, which was ineffective against biofilms even at the highest concentrations tested. The authors also demonstrated potent activity of the conjugate against persister cells, which are dormant cells that form spontaneously within a biofilm and are highly resistant to antibiotics. Kinetics assays revealed a remarkably fast killing rate, with death of MRSA persister cells occurring within 30 minutes of V-IDR1018 treatment. High efficacy of the conjugate was recapitulated in an organoid human skin model, with V-IDR1018 treatment demonstrating approximately 90% eradication efficacy when assessed against an MRSA biofilm. Furthermore, the conjugate decreased necrosis of the skin and reduced bacterial load in vivo when evaluated in a murine, high density skin abscess infection model using MRSA or S. epidermidis.

Beyond antimicrobial and antibiofilm activity, the immunomodulatory activity of V-IDR1018 was also notable. Treatment of peripheral blood mononuclear cells (PBMCs) with V-IDR1018 stimulated the release of cytokines and chemokines such as monocyte chemoattractant protein-1 (MCP-1), which could impact the recruitment of immune cells that have a role in the clearance of infection. Reassuringly, no statistically significant toxicity was observed for PBMCs at the highest concentration of V-IDR1018 tested.

Overall, the finding that the antibacterial, antibiofilm, and immune modulatory activities of vancomycin can be improved by conjugation to the host defence peptide IDR1018 is exciting. The conjugate may be effective against clinically relevant biofilm-forming bacteria including Staphylococcus species, but should be screened further in pre-clinical pharmacokinetic or pharmacodynamic studies.

 

Read more about the Hancock Lab’s ongoing research to address the growing antibiotic resistance problem.

 

Special thanks to Morgan Alford of the Hancock Lab for her comments and input on the piece.

 

References

  1. Murray, C. J., Ikuta, K. S., Swetschinski, L., Robles Aguilar, G., Gray, A., Han, C., Bisignano, C., Rao, P., Wool, E., Johnson, S. C., Chipeta, M. G., Fell, F., Hackett, S., Haines-Woodhouse, G., Kashef Hamadani, B. H., Kumaran, E. A. P., McManigal, B., Agarwal, R., Akech, S., . . . Antimicrobial Resistance Collaborators. (2022). Global burden of bacterial antimicrobial resistance in 2019: A systematic analysis. The Lancet (British Edition), 399(10325), 629-655. https://doi.org/10.1016/S0140-6736(21)02724-0
  2. Washington Post Editorial Board (2022, January 28). “Opinion: The shadow pandemic: Antibiotic resistance is growing”. Washington Post. https://www.washingtonpost.com/opinions/2022/01/28/shadow-pandemic-antibiotic-resistance-is-growing/
  3. Sharma, D., Misba, L., & Khan, A. U. (2019). Antibiotics versus biofilm: An emerging battleground in microbial communities. Antimicrobial Resistance & Infection Control, 8(1), 76-76. https://doi.org/10.1186/s13756-019-0533-3
  4. Etayash, H., Alford, M., Akhoundsadegh, N., Drayton, M., Straus, S. K., & Hancock, R. E. W. (2021). Multifunctional Antibiotic–Host defense peptide conjugate kills bacteria, eradicates biofilms, and modulates the innate immune response. Journal of Medicinal Chemistry, 64(22), 16854-16863. https://doi.org/10.1021/acs.jmedchem.1c01712