Cell-penetrating peptide and antibiotic combination therapy: a potential alternative to combat drug resistance in methicillin-resistant Staphylococcus aureus
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- 作者：Harmandeep Kaur Randhawa ; Ankur Gautam…
- 关键词：Methicillin ; resistant Staphylococcus aureus ; Drug resistance ; Drug delivery ; Cell ; penetrating peptides
- 刊名：Applied Microbiology and Biotechnology
- 出版年：2016
- 出版时间：May 2016
- 年：2016
- 卷：100
- 期：9
- 页码：4073-4083
- 全文大小：708 KB
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Ankur Gautam (2)
Minakshi Sharma (2)
Rakesh Bhatia (3)
Grish C. Varshney (3)
Gajendra Pal Singh Raghava (2)
Hemraj Nandanwar (1)
1. Bioactive Screening Laboratory, CSIR-Institute of Microbial Technology, Chandigarh, 160036, India
2. Bioinformatic Centre, CSIR-Institute of Microbial Technology, Chandigarh, 160036, India
3. Cell Biology and Immunology Laboratory, CSIR-Institute of Microbial Technology, Chandigarh, 160036, India - 刊物类别：Chemistry and Materials Science
- 刊物主题：Chemistry
Biotechnology
Microbiology
Microbial Genetics and Genomics - 出版者：Springer Berlin / Heidelberg
- ISSN：1432-0614
文摘
The diverse pattern of resistance by methicillin-resistant Staphylococcus aureus (MRSA) is the major obstacle in the treatment of its infections. The key reason of resistance is the poor membrane permeability of drug molecules. Over the last decade, cell-penetrating peptides (CPPs) have emerged as efficient drug delivery vehicles and have been exploited to improve the intracellular delivery of numerous therapeutic molecules in preclinical studies. Therefore, to overcome the drug resistance, we have investigated for the first time the effects of two CPPs (P3 and P8) in combination with four antibiotics (viz. oxacillin, erythromycin, norfloxacin, and vancomycin) against MRSA strains. We found that both CPPs internalized into the MRSA efficiently at very low concentration (<10 μM) which was non-toxic to bacteria as well as mammalian cells and showed no significant hemolytic activity. However, the combinations of CPPs (≤10 μM) and antibiotics showed high toxicity against MRSA as compared to antibiotics alone. The significant finding is that P3 and P8 could lower the MICs against oxacillin, norfloxacin, and vancomycin to susceptible levels (generally <1 μg/mL) for almost all five clinical isolates. Further, the bacterial cell death was confirmed by scanning electron microscopy as well as propidium iodide uptake assay. Simultaneously, time-kill kinetics revealed the increased uptake of antibiotics. In summary, CPPs assist to restore the effectiveness of antibiotics at much lower concentration, eliminate the antibiotic toxicity, and represent the CPP-antibiotic combination therapy as a potential novel weapon to combat MRSA infections.