Amphiphilic tetracationic porphyrins are exceptionally active antimicrobial photosensitizers: In vitro and in vivo studies with the free‐base and Pd‐chelate

Abstract

Antimicrobial photodynamic inactivation (aPDI) employs the combination of nontoxic photosensitizing dyes and visible light to kill pathogenic microorganisms regardless of drug-resistance, and can be used to treat localized infections.A meso-substituted tetra-methylpyridinium porphyrin with one methyl group replaced by a C12 alkyl chain (FS111) and its Pd-derivative (FS111-Pd) were synthesized and tested as broad-spectrum antimicrobial photosensitizers when excited by blue light (5 or 10 J/cm 2 ). Both compounds showed unprecedented activity, with the superior FS111-Pd giving 3 logs of killing at 1 nM, and eradication at 10 nM for Gram-positive methicillin-resistant Staphylococcus aureus. For the Gram-negative Escherichia coli, both compounds produced eradication at 100 nM, while against the fungal yeast Candida albicans, both compounds produced eradication at 500 nM. Both compounds could be categorized as generators of singlet oxygen (Φ Δ = 0.62 for FS111 and 0.71 for FS111-Pd). An in vivo study was carried out using a mouse model of localized infection in a partial thickness skin abrasion caused by bioluminescent Gram-negative uropathogenic E. coli. Both compounds were effective in reducing bioluminescent signal in a dose-dependent manner when excited by blue light (405 nm), but aPDI with FS111-Pd was somewhat superior both during light and in preventing recurrence during the 6 days following PDT. K E Y W O R D S amphiphilic tetracationic porphyrins, antimicrobial photodynamic inactivation, bioluminescence imaging, broad-spectrum activity, palladium-porphyrin, uropathogenic Escherichia coli infection

Antimicrobial Photodynamic Therapy Combined With Antibiotic in the Treatment of Rats With Third-Degree Burns

“…The aPDT efficacy shows a high correlation with the amount of the photosensitizer taken up by bacteria; accordingly, a long-enough incubation time is required ( Xuan et al, 2019 ). Bacterial culture was incubated with PPIX-MED (6.25 μM) for 320 min, and the absorption of the photosensitizer by the bacteria was experimentally determined by spectrophotometry ( Zhao et al, 2014 ).…”

Photodynamic disinfection and its role in controlling infectious diseases

“…One of the most successful cases of reducing G− bacterial infections on mice models is that of the non-symmetric tetra-cationic porphyrin complex with Pd(II), FS111-Pd (PS 36 ), recently published by Hamblin and co-workers [ 64 ]. Photodisinfection with FS111-Pd was more effective (complete inactivation 4 days after treatment with 50 μM photosensitizer concentration and 80 J/cm 2 ) than with the corresponding free base macrocycle.…”

“…This followed from research on PDDI using polycationic photosensitizer conjugates that remains inspiring [ 56 ]. Hamblin’s contributions to PDDI also include the disclosure of very potent photosensitizers with intense absorption in the near-infrared [ 57 ], important animal models to refine PDDI approaches [ 58 , 59 ], and methods to potentiate the efficacy of PDDI [ 60 ], among very numerous other contributions [ 31 , 42 , 61 – 64 ]. It is a great pleasure to contribute to a special issue celebrating the achievements of Mike Hamblin with this review on PDDI.…”

“…Various excellent reviews on PDDI have been published [ 32 , 65 – 77 ], including with a focus on the treatment of multi-resistant bacteria in planktonic suspensions or in biofilms [ 78 ], as well as fungi [ 79 ] and viruses [ 80 , 81 ]. Many efforts have been dedicated to the synthesis of photosensitizers and to new strategies for PDDI [ 62 , 64 , 66 , 67 , 82 , 83 ], including the combination with antimicrobials [ 32 , 84 , 85 ]. There is also an interesting literature on the use of blue light (400–450 nm) to excite endogenous photosensitizers that generate oxidative stress or to produce oxygen-independent DNA damage [ 86 ], but such approaches are intrinsically limited by the low penetration of blue light in human tissues.…”

Photodynamic inactivation of E. coli with cationic imidazolyl-porphyrin photosensitizers and their synergic combination with antimicrobial cinnamaldehyde

“…The clinical translation of PDI to photodisinfection of external wounds, such as diabetic foot ulcers, or of upper respiratory tract, ocular and buccal infections, is still limited by scientific challenges, namely, in the design and synthesis of photosensitizers at multigram scale, structural optimization to facilitate penetration of the double barrier present in Gram-negative bacteria, and effective infiltration in biofilms [7][8][9]. Studies with positively charged photosensitizers, such as cationic meso-(1-methylpyridinium-4-yl) [10][11][12][13][14][15][16][17][18][19][20][21] and meso-(4-N,N,N-trimethylammoniumphenyl) porphyrins [22][23][24], showed promising photoinactivation of E. coli and encouraged further work with cationic porphyrin derivatives.…”