Comparative Structure–Activity Analysis of the Antimicrobial Activity, Cytotoxicity, and Mechanism of Action of the Fungal Cyclohexadepsipeptides Enniatins and Beauvericin

Abstract

Filamentous fungi, although producing noxious molecules such as mycotoxins, have been used to produce numerous drugs active against human diseases such as paclitaxel, statins, and penicillin, saving millions of human lives. Cyclodepsipeptides are fungal molecules with potentially adverse and positive effects. Although these peptides are not novel, comparative studies of their antimicrobial activity, toxicity, and mechanism of action are still to be identified. In this study, the fungal cyclohexadepsipeptides enniatin (ENN) and beauvericin (BEA) were assessed to determine their antimicrobial activity and cytotoxicity against human cells. Results showed that these peptides were active against Gram-positive bacteria, Mycobacterium, and fungi, but not against Gram-negative bacteria. ENN and BEA had a limited hemolytic effect, yet were found to be toxic at low doses to nucleated human cells. Both peptides also interacted with bacterial lipids, causing low to no membrane permeabilization, but induced membrane depolarization and inhibition of macromolecules synthesis. The structure–activity analysis showed that the chemical nature of the side chains present on ENN and BEA (either iso-propyl, sec-butyl, or phenylmethyl) impacts their interaction with lipids, antimicrobial action, and toxicity.

Entomopathogenic fungi: unconventional applications

“…are other cyclic hexadepsipeptides with interesting properties. On the one hand, beauvericins contribute to the contamination of cereal crops worldwide, bioaccumulate in different tissues, and enter the food chain by polluting eggs, milk, meat, and plant products, consequently leading to apoptosis, production of reactive oxygen species (ROS), or mitochondrial damage (Olleik et al 2019). On the other hand, they have been shown to exert strong cytotoxic effect on tumor cells, inhibit the activity of Mycobacterium tuberculosis or Plasmodium falciparum, and restrict the activity of the cholesterol acyltransferase inhibitor (Urbaniak et al 2019;Jajić et al 2019).…”

Synthesis and Evaluation of the Antibacterial Activities of 13-Substituted Berberine Derivatives

“…Mycobacterium smegmatis (mc2155, ATCC 700084) was used as model of Mycobacterium species. Bacteria were cultured as previously described [ 15 , 16 , 17 , 18 ] Briefly, most of the bacterial strains were routinely grown on Luria Bertani (LB) agar plates and LB broth at 37 °C in aerobic condition except H. pylori that was grown in BHI in micro-aerobic condition using microaerobic BD GasPak generator (Sigma-Aldrich, Lyon, France). M. smegmatis was cultured in Middlebrook 7H10 agar plate and Middlebrook 7H10 broth at 37 °C in aerobic condition.…”

“…Antimicrobial activity of berberine and its derivatives was evaluated by determination of their minimal inhibitory concentration (MIC) using two-fold serial dilutions in bacterial liquid media following the National Committee of Clinical Laboratory Standards (NCCLS, 1997) as previously described [ 15 , 16 , 17 , 18 ]. Briefly, for most of the bacteria, single colonies of the different bacterial strains cultured on specific agar plates were used to inoculate 3 mL of Mueller-Hinton (MH), except C. difficile , C. perfringens , H. pylori , E. faecalis , and S. pyogenes that were cultured in 3 mL of BHI and or M. smegmatis that was cultured in 3 mL of Middlebrook 7H10 broth.…”

“…The toxicity of berberine and berberine’s derivatives on human cells was evaluated using resazurin assay as previously described [ 15 , 16 , 17 , 19 , 20 , 21 ]. Human cells used were BEAS (ATCC CRL-9609), Caco2 (ATCC HTB-37) and HepG2 (ATCC HB-8065) corresponding respectively to human airway epithelial cells, intestinal epithelial cells and liver cells.…”

“…Membrane permeabilization by berberine derivatives was evaluated using the cell-impermeable DNA/RNA probe propidium iodide as previously explained [ 15 , 16 , 22 , 23 ]. Logarithmic growing bacterial suspensions were prepared from overnight bacterial suspension by 1 in 10 dilution.…”