Novel Alligator Cathelicidin As-CATH8 Demonstrates Anti-Infective Activity against Clinically Relevant and Crocodylian Bacterial Pathogens

Abstract

Host defense peptides (HDPs) represent an alternative way to address the emergence of antibiotic resistance. Crocodylians are interesting species for the study of these molecules because of their potent immune system, which confers high resistance to infection. Profile hidden Markov models were used to screen the genomes of four crocodylian species for encoded cathelicidins and eighteen novel sequences were identified. Synthetic cathelicidins showed broad spectrum antimicrobial and antibiofilm activity against several clinically important antibiotic-resistant bacteria. In particular, the As-CATH8 cathelicidin showed potent in vitro activity profiles similar to the last-resort antibiotics vancomycin and polymyxin B. In addition, As-CATH8 demonstrated rapid killing of planktonic and biofilm cells, which correlated with its ability to cause cytoplasmic membrane depolarization and permeabilization as well as binding to DNA. As-CATH8 displayed greater antibiofilm activity than the human cathelicidin LL-37 against methicillin-resistant Staphylococcus aureus in a human organoid model of biofilm skin infection. Furthermore, As-CATH8 demonstrated strong antibacterial effects in a murine abscess model of high-density bacterial infections against clinical isolates of S. aureus and Acinetobacter baumannii, two of the most common bacterial species causing skin infections globally. Overall, this work expands the repertoire of cathelicidin peptides known in crocodylians, including one with considerable therapeutic promise for treating common skin infections.

LL-37: Structures, Antimicrobial Activity, and Influence on Amyloid-Related Diseases

“…Chicken cathelicidin AMPs or fowlicidins are extremely hemolytic although highly potent in killing wide-ranging pathogenic bacteria, including drug-resistant strains [91,92]. Table 2 summarizes a list of representative cathelicidin AMPs and their amino acid sequences, secondary structures, and activity profiles [86,87,89,[93][94][95][96][97][98][99][100][101][102][103][104][105][106][107]. @ G+ and G− represent Gram-positive and Gram-negative bacteria, respectively.…”

Multiple resistance factors collectively promote inoculum-dependent dynamic survival during antimicrobial peptide exposure inEnterobacter cloacae

“…AMPs also comprise a portion of our initial systemic response to infection [10]. Thousands of structurally unique AMPs have been isolated from other mammals, amphibians, reptiles (e.g., crocodylians), fish, birds, arachnids (tarantulas, araneomorph spiders, and scorpions), and mollusks [11][12][13]. Invertebrates lack adaptive immunity and rely heavily on AMPs to ward off invading microbes [14,15].…”

A 2022 Update on Computational Approaches to the Discovery and Design of Antimicrobial Peptides

“…Eighteen novel cathelicidin sequences were identified and subsequently synthetized and evaluated in vitro against planktonic and biofilm bacteria. Among the cathelicidins which displayed a broad-spectrum antimicrobial and antibiofilm activity against a range of antibiotic-resistant bacteria, As-CATH8 was highlighted because of its similar profile to the last-resort antibiotics vancomycin and polymyxin B [ 6 ]. An alternative method of searching for AMPs at the genomic level involves the in silico detection of corresponding biosynthetic gene clusters (BGCs).…”