Journal
INTERNATIONAL JOURNAL OF PHARMACEUTICS
Volume 608, Issue -, Pages -Publisher
ELSEVIER
DOI: 10.1016/j.ijpharm.2021.121097
Keywords
Tuberculosis; Antimicrobial peptide; HHC-8; MM-10; Nanoparticles; REMA (Resazurin Microtiter Assay Plate); Synergism
Categories
Funding
- Indian Council of Medical Research, New Delhi [5/8/5/68/Adhoc/2020/ECD-I]
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The treatment of tuberculosis is challenging due to the limitations of antibiotic effectiveness caused by the bacteria's lipid-rich cell wall and the development of resistance mutations. Antimicrobial peptides (AMPs) offer a new treatment strategy with promising potential when encapsulated in biocompatible polymers. This encapsulation method enhances antimicrobial activity and synergy with conventional antibiotics in combating mycobacteria.
Tuberculosis (TB) treatment has become a challenge because of the natural presence of multilayered cell wall rich in lipids which restrict antibiotic permeability within the bacteria. The development of mutations conferring resistance has aggravated the situation. Consequently, maximum pharmaceutical efforts are required to improve the treatment, and antimicrobial peptides (AMPs) with antimycobacterial activity can be exploited as a new treatment strategy against TB. The synergistic interaction between conventional antibiotics and AMPs has broadened its application landscape. To overcome peptide instability and bioavailability issues, encapsulation of these bioactive in biocompatible polymers was adopted. In this study, the effect of synthetic AMPs HHC-8 [KIWWWWRKR] and MM-10 [MLLKKLLKKM] encapsulated in poly (epsilon-caprolactone) nanoparticles (PCL-NPs) was evaluated against mycobacteria using REMA (Resazurin Microtiter Assay Plate) technique. PCL encapsulation allowed us to load the required amount of peptides, i.e. HHC-8 and MM-10, with an efficiency of similar to 18.9 +/- 5.24 and similar to 21.1 +/- 6.19 % respectively, and sphere size was around 376.5 +/- 14.9 nm and 289.87 +/- 17.98 nm for PCL-HHC-8-NPs and PCL-MM-10-NPs, respectively. Minimal degradation and sustained release of peptides from nanoparticles improved antimicrobial activity, decreasing the MIC50 from 75 mu g/ml to 18.75 mu g/ml against M. smegmatis and from 75 mu g/ml to 9 mu g/ml against M. tuberculosis, respectively. The combinatorial MIC assays of encapsulated AMP with rifampicin antibiotics against M. smegmatis showed synergism between AMP-PCL-NPs and antibiotics with fractional inhibitory concentrations (FICs) around similar to 0.09. The combinations of AMP NPs also demonstrated synergy against the mycobacteria. Our findings suggest that enhanced efficacy is due to protection offered by AMPs encapsulation resulting in augmentation of membrane permeation by AMPs and enhanced accumulation of antibiotics within mycobacteria resulting in synergy. The study findings might assist in the preclinical development of AMP for the fight against TB.
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