title: Carvacrol codrugs: a new approach in the antimicrobial plan.
abstract: OBJECTIVE
  The increasing prevalence of antibiotic-resistant bacterial infections led to identify alternative strategies for a novel therapeutic approach. In this study, we synthesized ten carvacrol codrugs - obtained linking the carvacrol hydroxyl group to the carboxyl moiety of sulphur-containing amino acids via an ester bond - to develop novel compounds with improved antimicrobial and antibiofilm activities and reduced toxicity respect to carvacrol alone.
  
  
  METHODS
  All carvacrol codrugs were screened against a representative panel of Gram positive (S. aureus and S. epidermidis), Gram negative (E. coli and P. aeruginosa) bacterial strains and C. albicans, using broth microdilution assays.
  
  
  RESULTS
  Results showed that carvacrol codrug 4 possesses the most notable enhancement in the anti-bacterial activity displaying MIC and MBC values equal to 2.5 mg/mL for all bacterial strains, except for P. aeruginosa ATCC 9027 (MIC and MBC values equal to 5 mg/mL and 10 mg/mL, respectively). All carvacrol codrugs 1-10 revealed good antifungal activity against C. albicans ATCC 10231. The cytotoxicity assay showed that the novel carvacrol codrugs did not produce human blood hemolysis at their MIC values except for codrugs 8 and 9. In particular, deepened experiments performed on carvacrol codrug 4 showed an interesting antimicrobial effect on the mature biofilm produced by E. coli ATCC 8739, respect to the carvacrol alone. The antimicrobial effects of carvacrol codrug 4 were also analyzed by TEM evidencing morphological modifications in S. aureus, E. coli, and C. albicans.
  
  
  CONCLUSIONS
  The current study presents an insight into the use of codrug strategy for developing carvacrol derivatives with antibacterial and antibiofilm potentials, and reduced cytotoxicity.
authors: Department of Pharmacy, University "G. d'Annunzio" Chieti-Pescara, Chieti, Italy.
authors: Ivana
authors: I
authors: Cacciatore
authors: Department of Pharmacy, University "G. d'Annunzio" Chieti-Pescara, Chieti, Italy.
authors: Mara
authors: M
authors: Di Giulio
authors: Department of Pharmacy, University "G. d'Annunzio" Chieti-Pescara, Chieti, Italy.
authors: Erika
authors: E
authors: Fornasari
authors: Department of Pharmacy, University "G. d'Annunzio" Chieti-Pescara, Chieti, Italy.
authors: Antonio
authors: A
authors: Di Stefano
authors: Department of Pharmacy, University "G. d'Annunzio" Chieti-Pescara, Chieti, Italy.
authors: Laura Serafina
authors: LS
authors: Cerasa
authors: Department of Pharmacy, University "G. d'Annunzio" Chieti-Pescara, Chieti, Italy.
authors: Lisa
authors: L
authors: Marinelli
authors: Department of Pharmacy, University "G. d'Annunzio" Chieti-Pescara, Chieti, Italy; Department of Molecular Biology and Genetics, Faculty of Science, Erzurum Technical University, Erzurum, Turkey.
authors: Hasan
authors: H
authors: Turkez
authors: Department of Pharmacy, University "G. d'Annunzio" Chieti-Pescara, Chieti, Italy.
authors: Emanuela
authors: E
authors: Di Campli
authors: Department of Pharmacy, University "G. d'Annunzio" Chieti-Pescara, Chieti, Italy.
authors: Soraya
authors: S
authors: Di Bartolomeo
authors: Institute of Molecular Genetics, National Research Council (CNR) section of Chieti, Chieti, Italy.
authors: Iole
authors: I
authors: Robuffo
authors: Department of Pharmacy, University "G. d'Annunzio" Chieti-Pescara, Chieti, Italy.
authors: Luigina
authors: L
authors: Cellini
mesh_terms: D000818:Animals; D000890:Anti-Infective Agents / Q000737:chemistry / Q000494:pharmacology* / Q000633:toxicity; D018441:Biofilms / Q000187:drug effects; D002176:Candida albicans / Q000187:drug effects* / Q000502:physiology; D000081007:Cymenes; D004912:Erythrocytes / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D006090:Gram-Negative Bacteria / Q000187:drug effects* / Q000502:physiology; D006094:Gram-Positive Bacteria / Q000187:drug effects* / Q000502:physiology; D006461:Hemolysis / Q000187:drug effects; D006801:Humans; D008826:Microbial Sensitivity Tests; D046529:Microscopy, Electron, Transmission; D039821:Monoterpenes / Q000737:chemistry / Q000494:pharmacology* / Q000633:toxicity; D051381:Rats
chemical_list: D000890:Anti-Infective Agents; D000081007:Cymenes; D039821:Monoterpenes; C073316:carvacrol