Sublethal Photodynamic Treatment Does Not Lead to Development of Resistance.

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2018-01

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Abstract

A promising new alternative approach for eradication of antibiotic-resistant strains is to expose microbes to photosensitizers, which upon illumination generate reactive oxygen species. Among the requirements for a potent, medically applicable photosensitizer, are high efficacy in killing microbes and low toxicity to the host. Since photodynamic treatment is based on production of reactive species which are potentially DNA damaging and mutagenic, it might be expected that under selective pressure, microbes would develop resistance. The aim of this study was to determine if antibacterial photodynamic treatment with a highly photoefficient photosensitizer, Zn(II) meso-tetrakis(N-n-hexylpyridinium-2-yl)porphyrin would lead to development of resistance. To answer that question, bacterial cultures were subjected to multiple cycles of sublethal photodynamic stress and regrowth, and to continuous growth under photodynamic exposure. Antibiotic-resistant Staphylococcus aureus and Escherichia coli clinical isolates were also tested for susceptibility to photodynamic inactivation and for development of resistance. Results demonstrated that multiple photodynamic exposures and regrowth of surviving cells or continuous growth under sublethal photodynamic conditions, did not lead to development of resistance to photosensitizers or to antibiotics. Antibiotic-resistant E. coli and S. aureus were as sensitive to photodynamic killing as were their antibiotic-sensitive counterparts and no changes in their sensitivity to antibiotics or to photodynamic inactivation after multiple cycles of photodynamic treatment and regrowth were observed. In conclusion, photosensitizers with high photodynamic antimicrobial efficiency can be used successfully for eradication of antibiotic-resistant bacterial strains without causing development of resistance.

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10.3389/fmicb.2018.01699

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Al-Mutairi, Rawan, Artak Tovmasyan, Ines Batinic-Haberle and Ludmil Benov (2018). Sublethal Photodynamic Treatment Does Not Lead to Development of Resistance. Frontiers in microbiology, 9. p. 1699. 10.3389/fmicb.2018.01699 Retrieved from https://hdl.handle.net/10161/21191.

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Scholars@Duke

Batinic-Haberle

Ines Batinic-Haberle

Professor Emeritus of Radiation Oncology

            A major interest of mine has been in the design and synthesis of Mn porphyrin(MnP)-based powerful catalytic antioxidants which helped establish structure-activity relationship (SAR). It relates the redox property of metalloporphyrins to their ability to remove superoxide. SAR has facilitated the design of redox-active therapeutics and served as a tool for mechanistic considerations. Importantly SAR parallels the magnitude of the therapeutic potential of SOD mimics and is valid for all classes of redox-active compounds. Two lead Mn porphyrins are already in five Phase II clinical trials (reviewed in Batinic-Haberle et al, Oxid Med Cell Longevity 2021). Recent research suggests immense potential of MnPs in cardiac diseases. MnTE-2-PyP (AEOL10113, BMX-010) prevents and treats cardiac arrhythmia, while MnTnBuOE-2-PyP (BMX-001) fully suppressed the development of aortic sclerosis in mice. The latter result is relevant to the cancer patients undergoing chemotherapy. In addition to breast cancer, in collaboration with Angeles Alvarez Secord, MD, MHSc, we have recently shown the anticancer effects of Mn porphyrin/ascorbate in cellular and mouse models of ovarian cancer.

            In parallel with synthetic efforts, I have also been interested in the mechanistic aspects of differential actions of Mn porphyrins in normal vs tumor tissue. In-depth studies of chemistry and biology of the reactions of MnPs with redox-active agents relevant to cancer therapy – ascorbate, chemotherapy and radiation – set ground for understanding the role of thermodynamics and kinetics in the mechanism of action of Mn porphyrins. Mechanistic studies have been revealed in Batinic-Haberle et al, Antioxidant Redox Signal 2018, Batinic-Haberle and Tome, Redox Biology 2019 and Batinic-Haberle et al Oxidative Medicine and Cellular Longevity 2021. My research has resulted in over 230 publications, 18 268 citations and an h-index of 64. For my achievements, I have been awarded the 2021 Discovery Award from the Society for Redox Biology and Medicine, SfRBM.

Additional Training

  • Postdoctoral fellowship with Professor Alvin Crumbliss in the field of Bioinorganic Chemistry, Department of Chemistry, Duke University
  • Postdoctoral fellowship with Professor Irwin Fridovich in the field of Redox Biology, Department of Biochemistry, Duke University School of Medicine

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