Molecules with a pronounced positive charge are able to effectively target bacteria (both Gram-positive and Gram-negative) for photodestruction. This is because the outer-membrane permeability barrier typical of Gram (-) bacteria is disrupted by cationic molecules, while Gram (+) species have negatively charged but permeable cell walls. We have discovered several novel classes of cationic PS;
Poly-L-lysine chlorin(e6) conjugates
Polyethylenimine chlorin(e6) conjugates
Quarternary ammonium or phosphonium salts of functionalized fullerenes
Selenium analogs of benzophenoxazine dyes
Cationic stable synthetic bacteriochlorins
Fullerenes with attached electron donor chains and light harvesting antennae.
Considerable data on the structure-function relationships of these molecules and their efficiency in photodynamic inactivation of a wide range of pathogenic microorganisms has been obtained. Gram-positive, Gram-negative bacteria, mycobacteria, yeasts, filamentous fungi and even bacterial endospores can all be effectively eradicated with more than 6 logs of killing.
Multi-antibiotic-resistant bacteria can be killed as easily as naive strains. Multi-drug resistance pumps can be overcome by specific small molecule inhibitors of efflux mechanisms. PDT can also photoinactivate virulence factors and toxins that are secreted by pathogens. We are investigating the role of different reactive oxygen species in microbial photoinactivation. PDT microbial killing may be potentiated by addition of small molecules such as iodide anion that can take advantage of free radical mechanisms.
We are also studying the role of multi-drug resistance efflux pumps in antimicrobial PDT and the design of efflux pump inhibitors to potentiate PDT.
Hamblin MR, O’Donnell DA, Murthy N, Rajagopalan K, Michaud N, Sherwood ME, Hasan T. Polycationic photosensitizer conjugates: photodynamic inactivation of bacteria depends on conjugate structure and Gram classification. J Antimicrob Chemother 2002;49(6):941-51.
Gad F, Zahra T, Hasan T, Hamblin MR. Photodynamic inactivation of Gram-positive pathogenic bacteria: effect of growth phase and extracellular slime. Antimicrob Agents Chemother, 2004; 48(6):2173-8.
Demidova TN, Hamblin MR. Photodynamic therapy targeted to pathogens. Int J Immunopathol Pharmacol 2004;17(3): 245-54.
Demidova TN, Hamblin MR. Effect of cell-photosensitizer binding and cell density on microbial photoinactivation. Antimicrob Agents Chemother; 2005;49(6):2329-35.
Demidova TN, Hamblin MR . Photodynamic inactivation of Bacillus spores mediated by phenothiazinium dyes. Appl Environ Microbiol, 2005, 71: 6918–6925.
Tegos GP, Demidova TN, Arcila-Lopez D, Lee H, Gali H, Wharton T, Hamblin MR. Cationic fullerenes are effective and selective antimicrobial photosensitizers. ChemBiol, 2005, 12: 1127-1135.
Tegos GP, Hamblin MR. Phenothiazinium antimicrobial photosensitizers are substrates of bacterial multidrug resistance pumps, Antimicrob Agents Chemother, 2006, 50: 196-203.
Tegos GP, Anbe M, Yang C, Demidova TN, Satti M, Mroz P, Janjua S, Gad F and Hamblin MR. Protease stable polycationic photosensitizer conjugates between polyethyleneimine and chlorin(e6) for broad spectrum antimicrobial photoinactivation. Antimicrob Agents Chemother, 2006, 50: 1402-1410.
Foley JW, Song X, Demidova TN, Jilal F, Hamblin MR. Synthesis and properties of benzo[a]phenoxazinium chalcogen analogs as novel broad-spectrum antimicrobial photosensitizers. J Med Chem. 2006, 49: 5291-5299.
Tang HM, Hamblin MR, ·Yow, CM. A comparative in vitro photoinactivation study of clinical isolates of multidrug-resistant pathogens,. J Infect Chemother, 2007, 13(2): 87-91.
Fuchs, BB, Tegos GP, Hamblin MR, and Mylonakis E. Susceptibility of Cryptococcus neoformans to photodynamic inactivation is associated with cell wall integrity. Antimicrob Agents Chemother, 2007, 51(8):2929-36. PMC1932496
Tegos GP, Masago K, Aziz F, Higginbotham A, Stermitz FR, Hamblin MR. Inhibitors of bacterial multidrug efflux pumps potentiate antimicrobial photoinactivation. Antimicrob Agents Chemother, 2008. 52(9): 3202-3209.
George S, Hamblin MR, Kishen A. Uptake pathways of anionic and cationic photosensitizers into bacteria. Photochem Photobiol Sci, 2009. 8(6), 788-795.
Huang L; Dai T; Hamblin MR. Antimicrobial photodynamic inactivation and photodynamic therapy for infections. Methods Mol Biol. 2010, 635: 155-73.
Kishen A, Upadya M, Tegos GP Hamblin MR. Efflux pump inhibitor potentiates photodynamic inactivation of Enterococcus faecalis biofilm. Photochem Photobiol. 2010. ;86(6):1343-9.
Garcez SG, Núñez SC, Baptista MS, Daghastanli NA, Itri R, Hamblin MR, Ribeiro MS. Antimicrobial mechanisms behind photodynamic effect in the presence of hydrogen peroxide. Photochem Photobiol Sci. 2010 10(4):483-90.
St Denis TG, Huang L, Dai T, Hamblin MR. Analysis of the Bacterial Heat Shock Response to Photodynamic Therapy-Mediated Oxidative Stress. Photochem Photobiol. 2011 87(3):707-13.
Huang L, Zhiyentayev T, Xuan Y, Azhibek D, Kharkwal GB, Hamblin MR. Photodynamic inactivation of bacteria using polyethylenimine–chlorin(e6) conjugates: Effect of polymer molecular weight, substitution ratio of chlorin(e6) and pH. Laser Surg Med, 2011, 43:313–323.
Fiamegos YC, Kastritis PL, Exarchou V, Han H, Bonvin MJ, Vervoot J, Lewis K, Hamblin MR, Tegos GP. Antimicrobial and efflux pump inhibitory activity of caffeoylquinic acids from Artemisia absinthium against Gram-positive pathogenic bacteria. PLoS ONE, 2011, 6(4): e18127
Prates RA, Kato IT, Ribeiro1 MS, Tegos GP, Hamblin MR. Influence of multidrug efflux systems on methylene blue-mediated photodynamic inactivation of Candida albicans. J Antimicrob Chemther. 2011, 66(7):1525-32
St. Denis TG, Dai T, Izikson A, Astrakas C, Anderson RR, Hamblin MR, Tegos GP. All you need is light: Antimicrobial photoinactivation as an evolving and emerging discovery strategy against infectious disease. Virulence, 2011, 2(6): 1-12
Tanaka M, Kinoshita M, Yoshihara Y, Shinomiya N, Seki S, Nemoto K, Hirayama T, Dai T, Huang L, Hamblin MR, Morimoto Y. Optimal photosensitizers for photodynamic therapy of infections should kill bacteria but spare neutrophils. Photochem Photobiol. 2012 Jan-Feb;88(1):227-32.
Vera DM, Haynes MH, Ball AR, Dai T, Astrakas C, Kelso MJ, Hamblin MR, Tegos GP. Strategies to potentiate antimicrobial photoinactivation by overcoming resistant phenotypes. Photochem Photobiol, 2012 Jan 88(3):499-511
Dai T, Fuchs BB, Coleman JJ, Prates RA, Astrakas A, St Denis TG, Ribeiro MS, Mylonakis E, Hamblin MR, Tegos GP. Concepts and principles of photodynamic therapy as an alternative antifungal discovery platform. Front. Microbio. 3:120.
Huang L, Xuan Y, Koide Y, Zhiyentayev T, Tanaka M, Hamblin MR. Type I and Type II mechanisms of antimicrobial photodynamic therapy: An in vitro study on Gram-negative and Gram-positive bacteria. Lasers Surg Med, 2012 Aug;44(6):490-9.
Shrestha A, Hamblin MR, Kishen A. Characterization of a conjugate between rose bengal and chitosan for targeted antibiofilm and tissue stabilization effects as a potential treatment of infected dentin. Antimicrob Agents Chemother. 2012 Jul 9. ;56(9):4876-84
St Denis TG, Dai T, Hamblin MR. Killing bacterial spores with blue light: when innate resistance meets the power of light. Photochem Photobiol. 2012 Sep 5.
Huang L, St Denis TG, Xuan Y, Tanaka M, Huang YY, Zadlo A, Sama T, Hamblin MR. Paradoxical potentiation of methylene blue-mediated antimicrobial photodynamic inactivation by sodium azide: role of ambient oxygen and azide radicals. Free Radical Biol Med, 2012. In press