PMID- 34103914 OWN - NLM STAT- MEDLINE DCOM- 20210618 LR - 20240226 IS - 1178-2013 (Electronic) IS - 1176-9114 (Print) IS - 1176-9114 (Linking) VI - 16 DP - 2021 TI - Therapeutic Potential of Novel Mastoparan-Chitosan Nanoconstructs Against Clinical MDR Acinetobacter baumannii: In silico, in vitro and in vivo Studies. PG - 3755-3773 LID - 10.2147/IJN.S296717 [doi] AB - PURPOSE: Acinetobacter baumannii antibiotic resistant infections in high-risk patients are a great challenge for researchers and clinicians worldwide. In an effort to achieve potent bactericidal outcomes, a novel chitosan-mastoparan nanoconstruct (Mast-Cs NC) was designed and assessed for its therapeutic potential through in silico, in vitro and in vivo experimentation against clinical multidrug-resistant (MDR) A. baumannii. METHODS: Optimized 3D structures of mastoparan and chitosan were coupled computationally through an ionic cross-linker to generate a circular ring of chitosan encasing mastoparan. The complex was assessed for interactions and stability through molecular dynamic simulation (MDS). Binding pocket analysis was used to assess the protease-peptide interface. Mast-Cs NC were prepared by the ionic gelation method. Mast-Cs NC were evaluated in vitro and in vivo for their therapeutic efficacy against drug-resistant clinical A. baumannii. RESULTS: MDS for 100 ns showed stable bonds between chitosan and mastoparan; the first at chitosan oxygen atom-46 and mastoparan isoleucine carbon atom with a distance of 2.77 A, and the second between oxygen atom-23 and mastoparan lysine nitrogen atom with a distance of 2.80 A, and binding energies of -3.6 and -7.4 kcal/mol, respectively. Mast-Cs complexes approximately 156 nm in size, with +54.9 mV zeta potential and 22.63% loading capacity, offered >90% encapsulation efficiency and were found to be geometrically incompatible with binding pockets of various proteases. The MIC(90) of Mast-Cs NC was significantly lower than that of chitosan (4 vs 512 mug/mL, respectively, p<0.05), with noticeable bacterial damage upon morphological analysis. In a BALB/c mouse sepsis model, a significant reduction in bacterial colony count in the Mast-Cs treated group was observed compared with chitosan and mastoparan alone (p<0.005). Mast-Cs maintained good biocompatibility and cytocompatibility. CONCLUSION: Novel mastoparan-loaded chitosan nanoconstructs signify a successful strategy for achieving a synergistic bactericidal effect and higher therapeutic efficacy against MDR clinical A. baumannii isolates. The Mast-Cs nano-drug delivery system could work as an alternative promising treatment option against MDR A. baumannii. CI - (c) 2021 Hassan et al. FAU - Hassan, Afreenish AU - Hassan A AUID- ORCID: 0000-0002-1802-1737 AD - Department of Microbiology, Armed Forces Institute of Pathology, National University of Medical Sciences, Rawalpindi, Pakistan. FAU - Ikram, Aamer AU - Ikram A AD - Department of Microbiology, Armed Forces Institute of Pathology, National University of Medical Sciences, Rawalpindi, Pakistan. FAU - Raza, Abida AU - Raza A AUID- ORCID: 0000-0002-4414-1070 AD - NILOP Nanomedicine Research Laboratories, National Institute of Lasers and Optronics College, Pakistan Institute of Engineering and Applied Sciences, Islamabad, Pakistan. FAU - Saeed, Sidra AU - Saeed S AD - NILOP Nanomedicine Research Laboratories, National Institute of Lasers and Optronics College, Pakistan Institute of Engineering and Applied Sciences, Islamabad, Pakistan. FAU - Zafar Paracha, Rehan AU - Zafar Paracha R AD - National University of Sciences and Technology, Islamabad, Pakistan. FAU - Younas, Zumara AU - Younas Z AD - Department of Microbiology, Armed Forces Institute of Pathology, National University of Medical Sciences, Rawalpindi, Pakistan. FAU - Khadim, Muhammad Tahir AU - Khadim MT AD - Department of Microbiology, Armed Forces Institute of Pathology, National University of Medical Sciences, Rawalpindi, Pakistan. LA - eng PT - Journal Article DEP - 20210601 PL - New Zealand TA - Int J Nanomedicine JT - International journal of nanomedicine JID - 101263847 RN - 0 (Anti-Bacterial Agents) RN - 0 (Intercellular Signaling Peptides and Proteins) RN - 0 (Peptides) RN - 0 (Wasp Venoms) RN - 72093-21-1 (mastoparan) RN - 9012-76-4 (Chitosan) RN - EC 3.4.- (Peptide Hydrolases) SB - IM MH - Acinetobacter baumannii/*drug effects/growth & development/isolation & purification MH - Adolescent MH - Adult MH - Animals MH - Anti-Bacterial Agents/pharmacology MH - Child MH - Child, Preschool MH - Chitosan/*chemistry MH - *Computer Simulation MH - Disease Models, Animal MH - Drug Resistance, Multiple, Bacterial/drug effects MH - Female MH - Humans MH - Intercellular Signaling Peptides and Proteins/*pharmacology MH - Male MH - Mice, Inbred BALB C MH - Microbial Sensitivity Tests MH - Middle Aged MH - Molecular Dynamics Simulation MH - Nanoparticles/*chemistry/ultrastructure MH - Peptide Hydrolases/metabolism MH - Peptides/chemistry/pharmacology MH - Wasp Venoms/*pharmacology MH - Young Adult MH - Mice PMC - PMC8179793 OTO - NOTNLM OT - Acinetobacter baumannii OT - antimicrobial peptides OT - antimicrobial resistance OT - chitosan OT - interactions OT - mastoparan OT - simulation OT - therapeutic efficacy COIS- All authors declare no conflicts of interest. EDAT- 2021/06/10 06:00 MHDA- 2021/06/22 06:00 PMCR- 2021/06/01 CRDT- 2021/06/09 06:41 PHST- 2020/12/13 00:00 [received] PHST- 2021/03/27 00:00 [accepted] PHST- 2021/06/09 06:41 [entrez] PHST- 2021/06/10 06:00 [pubmed] PHST- 2021/06/22 06:00 [medline] PHST- 2021/06/01 00:00 [pmc-release] AID - 296717 [pii] AID - 10.2147/IJN.S296717 [doi] PST - epublish SO - Int J Nanomedicine. 2021 Jun 1;16:3755-3773. doi: 10.2147/IJN.S296717. eCollection 2021.