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Biogenic Silver Nanoparticles Decorated with Methylene Blue Potentiated the Photodynamic Inactivation of Pseudomonas aeruginosa and Staphylococcus aureus.

ABSTRACT: The persistence of multidrug resistance among microorganisms has directed a mandate towards a hunt for the development of alternative therapeutic modalities. In this context, antimicrobial photodynamic therapy (aPDT) is sprouted as a novel strategy to mitigate biofilms and planktonic cells of pathogens. Nanoparticles (NPs) are reported with unique intrinsic and antimicrobial properties. Therefore, silver NPs (AgNPs) were investigated in this study to determine their ability to potentiate the aPDT of photosensitizer against Staphylococcus aureus and Pseudomonas aeruginosa. Biologically synthesized AgNPs were surface coated with methylene blue (MB) and studied for their aPDT against planktonic cells and biofilms of bacteria. The nano-conjugates (MB-AgNPs) were characterized for their size, shape and coated materials. MB-AgNPs showed significant phototoxicity against both forms of test bacteria and no toxicity was observed in the dark. Moreover, activity of MB-AgNPs was comparatively higher than that of the free MB, which concludes that MB-AgNPs could be an excellent alternative to combat antibiotic resistant bacteria.

SUBMITTER: Parasuraman P

PROVIDER: S-EPMC7464252 | biostudies-literature | 2020 Jul

REPOSITORIES: biostudies-literature

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Biogenic Silver Nanoparticles Decorated with Methylene Blue Potentiated the Photodynamic Inactivation of <i>Pseudomonas aeruginosa</i> and <i>Staphylococcus aureus</i>.

Parasuraman Paramanantham P R Y Thamanna T Shaji Chitra C Sharan Alok A Bahkali Ali H AH Al-Harthi Helal F HF Syed Asad A Anju V T VT Dyavaiah Madhu M Siddhardha Busi B

Pharmaceutics 20200729 8

The persistence of multidrug resistance among microorganisms has directed a mandate towards a hunt for the development of alternative therapeutic modalities. In this context, antimicrobial photodynamic therapy (aPDT) is sprouted as a novel strategy to mitigate biofilms and planktonic cells of pathogens. Nanoparticles (NPs) are reported with unique intrinsic and antimicrobial properties. Therefore, silver NPs (AgNPs) were investigated in this study to determine their ability to potentiate the aPD ...[more]

PMID: 32751176

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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.

Project description:Antimicrobial photodynamic inactivation (aPDI) and antimicrobial blue light (aBL) are considered low-risk treatments for the development of bacterial resistance and/or tolerance due to their multitargeted modes of action. In this study, we assessed the development of Staphylococcus aureus tolerance to these phototreatments. Reference S. aureus USA300 JE2 was subjected to 15 cycles of both sub-lethal aPDI (employing an exogenously administered photosensitizer (PS), i.e., rose Bengal (RB)) and sub-lethal aBL (employing endogenously produced photosensitizing compounds, i.e., porphyrins). We demonstrate substantial aPDI/aBL tolerance development and tolerance stability after 5 cycles of subculturing without aPDI/aBL exposure (the development of aPDI/aBL tolerance was also confirmed with the employment of clinical MRSA and MSSA strain as well as other representatives of Gram-positive microbes, i.e. Enterococcus faecium and Streptococcus agalactiae). In addition, a rifampicin-resistant (RIFR) mutant selection assay showed an increased mutation rate in S. aureus upon sub-lethal phototreatments, indicating that the increased aPDI/aBL tolerance may result from accumulated mutations. Moreover, qRT-PCR analysis following sub-lethal phototreatments demonstrated increased expression of umuC, which encodes stress-responsive error-prone DNA polymerase V, an enzyme that increases the rate of mutation. Employment of recA and umuC transposon S. aureus mutants confirmed SOS-induction dependence of the tolerance development. Interestingly, aPDI/aBL-tolerant S. aureus exhibited increased susceptibility to gentamicin (GEN) and doxycycline (DOX), supporting the hypothesis of genetic alterations induced by sub-lethal phototreatments. The obtained results indicate that S. aureus may develop stable tolerance to studied phototreatments upon sub-lethal aPDI/aBL exposure; thus, the risk of tolerance development should be considered significant when designing aPDI/aBL protocols for infection treatments in vitro and in clinical settings.

Project description:Staphylococcus aureus is an opportunistic pathogen with a clinical spectrum ranging from asymptomatic skin colonization to invasive infections. While traditional antibiotic therapies can be effective against S. aureus, the increasing prevalence of antibiotic-resistant strains results in treatment failures and high mortality rates. Photodynamic inactivation (PDI) is an innovative and promising alternative to antibiotics. While progress has been made in our understanding of the bacterial response to PDI, major gaps remain in our knowledge of PDI tolerance, the global cellular response, and adaptive genomic mutations acquired as a result of PDI. To address these gaps, S. aureus HG003 and isogenic mutants with mutations in agr, mutS, mutL, and mutY exposed to single or multiple doses of PDI were assessed for survival and tolerance and examined by global transcriptome and genome analyses to identify regulatory and genetic adaptations that contribute to tolerance. Pathways in inorganic ion transport, oxidative response, DNA replication recombination and repair, and cell wall and membrane biogenesis were identified in a global cellular response to PDI. Tolerance to PDI was associated with superoxide dismutase and the S. aureus global methylhydroquinone (MHQ)-quinone transcriptome network. Genome analysis of PDI-tolerant HG003 identified a nonsynonymous mutation in the quinone binding domain of the transcriptional repressor QsrR, which mediates quinone sensing and oxidant response. Acquisition of a heritable QsrR mutation through repeated PDI treatment demonstrates selective adaption of S. aureus to PDI. PDI tolerance of a qsrR gene deletion in HG003 confirmed that QsrR regulates the S. aureus response to PDI.IMPORTANCE Staphylococcus aureus can cause disease at most body sites, with illness ranging from asymptomatic infection to death. The increasing prevalence of antibiotic-resistant strains results in treatment failures and high mortality rates. S. aureus acquires resistance to antibiotics through multiple mechanisms, often by genetic variation that alters antimicrobial targets. Photodynamic inactivation (PDI), which employs a combination of a nontoxic dye and low-intensity visible light, is a promising alternative to antibiotics that effectively eradicates S. aureus in human infections when antibiotics are no longer effective. In this study, we demonstrate that repeated exposure to PDI results in resistance of S. aureus to further PDI treatment and identify the underlying bacterial mechanisms that contribute to resistance. This work supports further analysis of these mechanisms and refinement of this novel technology as an adjunctive treatment for S. aureus infections.

Dataset Information

Biogenic Silver Nanoparticles Decorated with Methylene Blue Potentiated the Photodynamic Inactivation of Pseudomonas aeruginosa and Staphylococcus aureus.

Publications

Biogenic Silver Nanoparticles Decorated with Methylene Blue Potentiated the Photodynamic Inactivation of <i>Pseudomonas aeruginosa</i> and <i>Staphylococcus aureus</i>.

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