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.

摘要

对常用抗生素具有抗性的细菌菌株的扩散促使新型抗菌化合物的发展。理想情况下，这些新型抗微生物药应不易产生耐药性。肽聚糖降解酶是一类有前途的化合物，与传统使用的抗生素相比，其作用方式根本不同。作用机制的差异意味着抵抗机制及其出现机会的差异。为了严格评估对肽聚糖降解酶产生抗药性的潜力，我们回顾了体外对这些酶产生抗药性的现有证据，以及对溶菌酶，细菌素，自溶素和噬菌体内溶素的耐药机制。我们得出结论，对肽聚糖降解酶具有抗性的遗传决定因素不太可能从头出现。但是，对这些酶的抗性可能会通过内在抗性和易感物种之间的水平转移而传播。最后，我们推测与传统抗生素相比，基于肽聚糖降解酶的治疗药物成本较高，可导致较少的误用，进而导致较低的选择压力，从而使这些抗菌药物不易产生耐药性。