Ceragenins and antimicrobial peptides kill bacteria through distinct mechanisms

Abstract

Ceragenins are a family of synthetic amphipathic molecules designed to mimic the properties of naturally-occurring cationic antimicrobial peptides (CAMPs). Although ceragenins have potent antimicrobial activity, whether their mode of action is similar to that of CAMPs has remained elusive. Here we report the results of a comparative study of the bacterial responses to two well-studied CAMPs, LL37 and colistin, and two ceragenins with related structures, CSA13 and CSA131. Using transcriptomic and proteomic analyses, we found that Escherichia coli responds similarly to both CAMPs and ceragenins by inducing a Cpx envelope stress response. However, whereas E. coli exposed to CAMPs increased expression of genes involved in colanic acid biosynthesis, bacteria exposed to ceragenins specifically modulated functions related to phosphate transport, indicating distinct mechanisms of action between these two classes of molecules. Although traditional genetic approaches failed to identify genes that confer high-level resistance to ceragenins, using a Clustered Regularly Interspaced Short Palindromic Repeats interference (CRISPRi) approach we identified E. coli essential genes that when knocked down modify sensitivity to these molecules. Comparison of the essential gene-antibiotic interactions for each of the CAMPs and ceragenins identified both overlapping and distinct dependencies for their antimicrobial activities. Overall, this study indicates that while some bacterial responses to ceragenins overlap with those induced by naturally-occurring CAMPs, these synthetic molecules target the bacterial envelope using a distinctive mode of action.

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“…Similar to other aminosterols, ceragenins elicit bacterial membrane permeabilization and act synergetically with other antibiotics and antimicrobials, which was confirmed for colistin, tobramycin, ciprofloxacin, LL-37, lysozyme, and lactoferrin [99,235]. Importantly, ceragenins elicit different gene responses in E. coli as compared to cationic antimicrobial peptides, which is associated with a lower level of resistance [236]. Another important benefit of ceragenins is their improved activity in cystic fibrosis sputum.…”

Ceragenin CSA-13 displays high antibacterial efficiency in a mouse model of urinary tract infection

“…Other publications also clearly show the effective action of CSAs against E. coli strains 17,32,33 . Importantly, CSA-13 maintains its activity also in the presence of urine (Table 2).…”

“…Importantly, CSA-13 maintains its activity also in the presence of urine (Table 2). In one of the previous studies, Mitchell et al 32 presented that ceragenins have a distinctive mode of action and they propose a model in which ceragenins cross the outer layers of Gram-negative bacterial envelope and disrupt the inner membrane. Because the bacterial membrane and its phospholipid composition is a similar structural feature between Gram-positive and Gram-negative bacteria, and because resistance to drugs that target the membrane will require significant changes in membrane structure and composition, the membrane is an www.nature.com/scientificreports/ intriguing target for compounds such as ceragenins 34 .…”