RESUMO
Antibiotic resistance is an increasing global problem and therapeutic alternatives to traditional antibiotics are needed. Antimicrobial and host defense peptides represent an attractive source for new therapeutic strategies, given their wide range of activities including antimicrobial, antitumoral and immunomodulatory. Insects produce several families of these peptides, including cecropins. Herein, we characterized the sequence, structure, and biological activity of three cecropins called satanin 1, 2, and curvicin, found in the transcriptome of two dung beetle species Dichotomius satanas and Onthophagus curvicornis. Sequence and circular dichroism analyses show that they have typical features of the cecropin family: short length (38-39 amino acids), positive charge, and amphipathic α-helical structure. They are active mainly against Gram-negative bacteria (3.12-12.5 µg/mL), with low toxicity on eukaryotic cells resulting in high therapeutic indexes (TI > 30). Peptides also showed effects on TNFα production in LPS-stimulated PBMCs. The biological activity of Satanin 1, 2 and Curvicin makes them interesting leads for antimicrobial strategies.
Assuntos
Antibacterianos/farmacologia , Cecropinas/química , Cecropinas/farmacologia , Neutrófilos/efeitos dos fármacos , Células A549 , Animais , Antibacterianos/química , Cecropinas/isolamento & purificação , Linhagem Celular Tumoral , Chlorocebus aethiops , Dicroísmo Circular , Besouros , Bactérias Gram-Negativas/efeitos dos fármacos , Hemólise/efeitos dos fármacos , Humanos , Testes de Sensibilidade Microbiana , Mycobacterium tuberculosis/efeitos dos fármacos , Mycobacterium tuberculosis/isolamento & purificação , Neutrófilos/metabolismo , Tuberculose/tratamento farmacológico , Tuberculose/microbiologia , Fator de Necrose Tumoral alfa/metabolismo , Células VeroRESUMO
Cecropin 3 (Ccrp3) is an antimicrobial peptide from Anopheles albimanus, which is expressed during Plasmodium berghei infection. Here, we report that synthetic Ccrp3, aside from antibacterial activity, also shows cardio regulatory functions. In rats, Ccrp3 significantly diminishes blood pressure as well as the heartbeat frequency at nanomolar concentration. Ccrp3 affect the rat cardiac muscle mitochondria, inducing uncoupling of oxidative phosphorylation, oxygen consumption and transport of Ca(2). Ccrp3 treatment of the mitochondria causes mitochondrial damage promoting oxidative stress, causing overproduction of reactive oxygen species (ROS) and inhibition of superoxide dismutase. At nM concentration, Ccrp3 inhibits superoxide dismutase activity through direct interaction, diminishing by its enzymatic activity. Ccrp3 induces the release of the pro-apoptotic marker Bax from the mitochondria. Altogether, these results suggest that Ccrp3 pro-oxidative activity on cardiac muscle mitochondria could be responsible for triggering the heartbeat frequency and blood pressure lowering observed the Ccrp3 injected rats.