Resistance to peptidoglycan-degrading enzymes

Abstract

The spread of bacterial strains resistant to commonly used antibiotics urges the development of novel antibacterial compounds. Ideally, these novel antimicrobials should be less prone to the development of resistance. Peptidoglycan-degrading enzymes are a promising class of compounds with a fundamentally different mode of action compared to traditionally used antibiotics. The difference in the mechanism of action implies differences both in the mechanisms of resistance and the chances of its emergence. To critically assess the potential of resistance development to peptidoglycan-degrading enzymes, we review the available evidence for the development of resistance to these enzymes in vitro, along with the known mechanisms of resistance to lysozyme, bacteriocins, autolysins, and phage endolysins. We conclude that genetic determinants of resistance to peptidoglycan-degrading enzymes are unlikely to readily emerge de novo. However, resistance to these enzymes would probably spread by the horizontal transfer between intrinsically resistant and susceptible species. Finally, we speculate that the higher cost of the therapeutics based on peptidoglycan degrading enzymes compared to classical antibiotics might result in less misuse, which in turn would lead to lower selective pressure, making these antibacterials less prone to resistance development.

Keywords:

• Antimicrobial enzyme
• endolysin
• peptidoglycan
• enzybiotic
• resistance

Acknowledgements

The authors wish to express their gratitude to the two anonymous reviewers for their careful reading of the manuscript and critical comments. We are particularly thankful to Reviewer 1 for suggesting important references that we had missed during the preparation of the manuscript and insightful ideas that greatly improved this review.

Disclosure statement

The authors report no conflict of interest.

Additional information

Funding

This work was funded by the Russian Science Foundation under Grant № 18-15-00235.