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Cell-penetrating peptide and antibiotic combination therapy: a potential alternative to combat drug resistance in methicillin-resistant Staphylococcus aureus

  • Applied microbial and cell physiology
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Abstract

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.

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Acknowledgments

Authors HN and GPSR acknowledge the CSIR for Network Project (BSC121) grant to support this study. We are also thankful to Prof. Varsha Gupta, Professor in Clinical Microbiology, Govt. Medical College & Hospital, Sector 32, Chandigarh for providing clinical strains for this study.

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Authors and Affiliations

  1. Bioactive Screening Laboratory, CSIR-Institute of Microbial Technology, Chandigarh, 160036, India

    Harmandeep Kaur Randhawa & Hemraj Nandanwar

  2. Bioinformatic Centre, CSIR-Institute of Microbial Technology, Chandigarh, 160036, India

    Ankur Gautam, Minakshi Sharma & Gajendra Pal Singh Raghava

  3. Cell Biology and Immunology Laboratory, CSIR-Institute of Microbial Technology, Chandigarh, 160036, India

    Rakesh Bhatia & Grish C. Varshney

Authors
  1. Harmandeep Kaur Randhawa
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  2. Ankur Gautam
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  3. Minakshi Sharma
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  4. Rakesh Bhatia
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  5. Grish C. Varshney
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  6. Gajendra Pal Singh Raghava
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  7. Hemraj Nandanwar
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Corresponding authors

Correspondence to Gajendra Pal Singh Raghava or Hemraj Nandanwar.

Ethics declarations

This article does not contain any studies with animals performed by any of the authors. This study was approved by the Institutional Biosafety Commitee.

Funding

This study was funded by Council of Scientific and Industrial Research (BSC0121 and BSC0121H).

Conflict of interest

There is no conflict of interest

Additional information

Harmandeep Kaur Randhawa and Ankur Gautam equally contributed to this paper.

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Randhawa, H.K., Gautam, A., Sharma, M. et al. Cell-penetrating peptide and antibiotic combination therapy: a potential alternative to combat drug resistance in methicillin-resistant Staphylococcus aureus . Appl Microbiol Biotechnol 100, 4073–4083 (2016). https://doi.org/10.1007/s00253-016-7329-7

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  • DOI: https://doi.org/10.1007/s00253-016-7329-7

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