Abstract
Previously, we identified that a cyclic hexapeptide AOA-2 inhibited the interaction of Gram-negative bacilli (GNB) like Acinetobacter baumannii, Pseudomonas aeruginosa, and Escherichia coli to host cells thereby preventing the development of infection in vitro and in a murine sepsis peritoneal model. In this work, we aimed to evaluate in vitro a library of AOA-2 derivatives in order to improve the effect of AOA-2 against GNB infections. Ten AOA-2 derivatives were synthetized for the in vitro assays. Their toxicities to human lung epithelial cells (A549 cells) for 24 h were evaluated by determining the A549 cells viability using 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay. The effect of these peptide derivatives and AOA-2 at 250, 125, 62.5, and 31.25 μg/mL on the attachment of A. baumannii ATCC 17978, P. aeruginosa PAO1 and E. coli ATCC 25922 strains to A549 cells was characterized by adherence and viability assays. None of the 10 derivatives showed toxicity to A549 cells. RW01 and RW06 have reduced more the adherence of ATCC 17978, PAO1 and ATCC 2599 strains to A549 cells when compared with the original compound AOA-2. Moreover, both peptides have increased slightly the viability of infected A549 cells by PAO1 and ATCC 25922 than those observed with AOA-2. Finally, RW01 and RW06 have potentiated the activity of colistin against ATCC 17978 strain in the same level with AOA-2. The optimization program of AOA-2 has generated two derivatives (RW01 and RW06) with best effect against interaction of GNB with host cells, specifically against P. aeruginosa and E. coli.
Highlights
Multidrug resistance (MDR) in Gram-negative bacilli (GNB) is a current threat in global health that requires effective and urgent solutions, being a global priority for WHO (Tacconelli et al, 2018)
The optimization of the AOA-2 peptide was carried out through an iterative computational design process. This computational design was based on the use of docking techniques with flexible side chains and molecular dynamics, using the data on the interaction of AOA-2 and outer membrane protein A (OmpA) in detailed (VilaFarrés et al, 2017)
First we showed that AOA-2, RW01, RW02, RW03, and RW06 at 250 μg/mL reduced the adherence of A. baumannii to 36.62, 26.18, 43.58, 55.47, and 32.83%, respectively, the adherence of P. aeruginosa to 84.47, 40.08, 42.51, 20.71, and 31.14%, respectively and the adherence of E. coli to 65.05, 66.66, 61.11, 29.62, and 44.44%, respectively
Summary
Multidrug resistance (MDR) in Gram-negative bacilli (GNB) is a current threat in global health that requires effective and urgent solutions, being a global priority for WHO (Tacconelli et al, 2018). The success of GNB as a community and nosocomial pathogen is attributed to its resistant to several antibiotic families. Whole-genome sequencing studies involving the GNB have demonstrated not AOA-2 Derivatives for Treatment of GNB Infections only a vast array of antibiotic drug resistance determinants and many pathogenicity islands OmpA is a β-barrel porin highly conserved among bacterial species, especially among Gram-negative organisms It has been suggested to have involvement in the adherence to epithelia (Gaddy et al, 2009), translocation into the epithelial cell nucleus (Choi et al, 2008), induction of epithelial cell death (Choi et al, 2005), biofilm formation (Gaddy et al, 2009), and binding to factor H, which may allow A. baumannii to develop serum resistance (Kim et al, 2009)
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
