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Potentiation of antimicrobial photodynamic inactivation mediated by a cationic fullerene by added iodide: in vitro and in vivo studies.

ABSTRACT: Antimicrobial photodynamic inactivation with fullerenes bearing cationic charges may overcome resistant microbes.We synthesized C60-fullerene (LC16) bearing decaquaternary chain and deca-tertiary-amino groups that facilitates electron-transfer reactions via the photoexcited fullerene. Addition of the harmless salt, potassium iodide (10 mM) potentiated the ultraviolet A (UVA) or white light-mediated killing of Gram-negative bacteria Acinetobacter baumannii, Gram-positive methicillin-resistant Staphylococcus aureus and fungal yeast Candida albicans by 1-2+ logs. Mouse model infected with bioluminescent Acinetobacter baumannii gave increased loss of bioluminescence when iodide (10 mM) was combined with LC16 and UVA/white light.The mechanism may involve photoinduced electron reduction of (1)(C60>)* or (3)(C60>)* by iodide producing I· or I2 followed by subsequent intermolecular electron-transfer events of (C60>)-· to produce reactive radicals.

SUBMITTER: Zhang Y

PROVIDER: S-EPMC4899971 | biostudies-literature | 2015 Mar

REPOSITORIES: biostudies-literature

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Potentiation of antimicrobial photodynamic inactivation mediated by a cationic fullerene by added iodide: in vitro and in vivo studies.

Zhang Yunsong Y Dai Tianhong T Wang Min M Vecchio Daniela D Chiang Long Y LY Hamblin Michael R MR

Nanomedicine (London, England) 20150301 4

<h4>Background</h4>Antimicrobial photodynamic inactivation with fullerenes bearing cationic charges may overcome resistant microbes.<h4>Methods & results</h4>We synthesized C60-fullerene (LC16) bearing decaquaternary chain and deca-tertiary-amino groups that facilitates electron-transfer reactions via the photoexcited fullerene. Addition of the harmless salt, potassium iodide (10 mM) potentiated the ultraviolet A (UVA) or white light-mediated killing of Gram-negative bacteria Acinetobacter bauma ...[more]

PMID: 25723093

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Project description:It is known that multiple cationic charges are required to produce broad-spectrum antimicrobial photosensitizers (PS) for photodynamic inactivation (aPDI) or photodynamic therapy of bacteria and fungi. In the present study we describe the synthesis and aPDI testing of a set of derivatives prepared from the parent pheophytin molecule with different numbers of attached side arms (1-3) each consisting of five quaternized cationic groups (pentacationic), producing the corresponding [Zn2+]pheophorbide-a-N(C2N+C1C3)5 (Zn-Phe-N5+, 5 charges), [Zn2+]chlorin e6-[N(C2N+C1C3)5]2 (Zn-Chl-N10+, 10 charges) and [Zn2+]mesochlorin e6-[N(C2N+C1C3)5]3 (Zn-mChl-N15+, 15 charges). Moreover, a conjugate between Zn-Phe-N5+ and the antibiotic vancomycin called Van-[Zn2+]-m-pheophorbide-N(C2N+C1C3)5 (Van-Zn-mPhe-N5+) was also prepared. The aPDI activities of all compounds were based on Type-II photochemistry (1O2 generation). We tested these compounds against Gram-positive methicillin-resistant Staphylococcus aureus (MRSA), Gram-negative Escherichia coli, and the fungal yeast Candida albicans. All three compounds were highly active against MRSA, giving eradication (≥6 logs of killing) with <1.0 μM and 10 J cm-2 of 415 nm light. The order of activity was Zn-Phe-N5+ > Zn-Chl-N10+ > Zn-mChl-N15+. In the case of E coli the activity was much lower (eradication was only possible with 50 μM Zn-mChl-N15+ and 20 J cm-2). The order of activity was the reverse of that found with MRSA (Zn-mChl-N15+ > Zn-Chl-N10+ > Zn-Phe-N5+). Activity against C. albicans was similar to E. coli with Zn-mChl-N15+ giving eradication. The activity of Van-Zn-mPhe-N5+ was generally lower than that of Zn-Phe-N5+ (except for E. coli). Red (660 nm) light was also effective as might be expected from the absorption spectra. An initial finding that Van-Zn-mPhe-N5+ might have higher activity against vancomycin resistant Enterococcus fecium (VRE) strains (compared to vancomycin sensitive strains) was disproved when it was found that VRE strains were also more sensitive to aPDI with Zn-Phe-N5+. The minimum inhibitory concentrations of Van-Zn-mPhe-N5+ were higher than those of Van alone, showing that the antibiotic properties of the Van moiety were lessened in the conjugate. In conclusion, Zn-Phe-N5+ is a highly active PS against Gram-positive species and deserves further testing. Increasing the number of cationic charges increased aPDI efficacy on C. albicans and Gram-negative E. coli.

Project description:A promising alternative to antibiotics for treatment of Staphylococcus aureus infections is photodynamic inactivation (PDI), which employs a photosensitizer (PS) that produces cytotoxic reactive oxygen species (ROS) when exposed to molecular oxygen and antimicrobial blue light in the spectrum of 400-470 nm. Although the precise mechanistic basis of PDI has not been defined, the formation of ROS and free radicals that oxidize a number of cellular targets, including membrane lipids, damage to proteins and nucleic acids result in inactivation of essential cellular functions and subsequent cell death. Because PDI is non-selective and affects multiple cellular targets, development of resistance or tolerance to PDI has been considered to be unlikely and attempts to induce S. aureus resistance or tolerance upon repeated sub-lethal doses of PDI have not succeeded. However, multiple aspects of PDI suggest that development of tolerance is highly probable, in particular when PDI is used for treatment of infections where the environment at the infection site prevents penetration of PDI at a level sufficient to cause death of all bacteria and with tolerant phenotypes emerging from the surviving bacteria. In this study, we sought to identify the mechanisms that contribute to PDI tolerance in S. aureus. S. aureus HG003 and the isogenic HG003DmutSL strain with defects in DNA mismatch repair were used to evaluate the response of S. aureus and the roles of DNA mismatch repair and gene regulatory networks to repeated sublethal doses of PDI. Global transcriptome and genome analyses were used in an agnostic approach to identify the underlying transcriptional responses and genetic adaptations that occur as a result of repeated PDI and contribute to PDI tolerance. Our results reveal multiple metabolic, transport and cell wall biogenesis pathways that contribute to PDI tolerance, and a S. aureus regulatory gene likely responsible for the adaptive transcriptional response to PDI.

Dataset Information

Potentiation of antimicrobial photodynamic inactivation mediated by a cationic fullerene by added iodide: in vitro and in vivo studies.

Publications

Potentiation of antimicrobial photodynamic inactivation mediated by a cationic fullerene by added iodide: in vitro and in vivo studies.

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