The Diversified O-Superfamily in Californiconus californicus Presents a Conotoxin with Antimycobacterial Activity

Abstract

Californiconus californicus, previously named Conus californicus, has always been considered a unique species within cone snails, because of its molecular, toxicological and morphological singularities; including the wide range of its diet, since it is capable of preying indifferently on fish, snails, octopus, shrimps, and worms. We report here a new cysteine pattern conotoxin assigned to the O1-superfamily capable of inhibiting the growth of Mycobacterium tuberculosis (Mtb). The conotoxin was tested on a pathogen reference strain (H37Rv) and multidrug-resistant strains, having an inhibition effect on growth with a minimal inhibitory concentration (MIC) range of 3.52–0.22 μM, similar concentrations to drugs used in clinics. The peptide was purified from the venom using reverse phase high-performance liquid chromatography (RP-HPLC), a partial sequence was constructed by Edman degradation, completed by RACE and confirmed with venom gland transcriptome. The 32-mer peptide containing eight cysteine residues was named O1_cal29b, according to the current nomenclature for this type of molecule. Moreover, transcriptomic analysis of O-superfamily toxins present in the venom gland of the snail allowed us to assign several signal peptides to O2 and O3 superfamilies not described before in C. californicus, with new conotoxins frameworks.

Identification of Novel Conotoxin Precursors from the Cone Snail Conus spurius by High-Throughput RNA Sequencing

“…O01) in C. spurius has the framework C-C-CC-C-C-C-C, which has been reported in C. ermineus [25] and C. litteratus [26]. Recently, a precursor with a new Cys framework (C-C-CCC-C-C-C-CC), O2_cal30, was reported for Californiconus californicus [36], another predatory sea cone snail.…”

Synthesis and evaluation of a novel analgesic conotoxin Lt7b that inhibits calcium currents and increases sodium currents

“…To date, four of the seven reported O 2 ‐superfamily conotoxins have shown significant functional diversity (Table S1). 7,8 TxVIIA and PnVIIA are agonists of neuronal pacemaker cation currents; Lt7a blocks voltage‐sensitive sodium channels; PiVIIA increases Ca 2+ currents. The functions of As7a and De7a are still unknown and might also affect voltage‐gated nonspecific cation pacemaker channels 9,10 .…”

Combined Proteotranscriptomic-Based Strategy to Discover Novel Antimicrobial Peptides from Cone Snails

“…Conotoxins are the disulfide-rich peptides found in the venom of cone snails responsible for their toxicity [ 17 , 60 ]. They are produced in the venom gland as precursors, which generally contain a signal, a pro, and a mature sequence.…”

“…Compared to other animals like scorpions or spiders, the antimicrobial peptides from cone snails have received little attention [ 16 , 17 , 18 ]. For example, the investigation of scorpion venoms led to the discovery of Hadrurin, Scorpine, Vejovine, StCT2, Pandinin 1, and Pandinin 2, which are effective antimicrobial peptides [ 19 , 20 , 21 , 22 , 23 ].…”