Investigation into the toxicity and DNA interactive properties of a range of cationic photosensitisers with potential application to photodynamic antimicrobial chemotherapy

The emergence of bacterial strains with resistance to traditional antibiotics has necessitated fresh approaches to the treatment of infections. In the present study, the therapeutic potential of a series of phenothiazinium-based photo-sensitisers (PhBP5) to act as novel antibacterial agents is investigated. It is shown that these PhBPs possess maximal light adsorption characteristics (A), which range from 536 nm - 648 nm, a characteristic, therapeutically desirable for the topical administration of photosenstisers. The lipophilicity (!ogP) of the PhBPs is generally 0.7 or above, showing these photosensitisers to be lipophilic and suggesting an ability to interact with either lipid or membranes. Additionally, the singlet oxygen yield ((D 1 ) of these PhBPs is generally 0.77 or above, consistent with high levels of singlet oxygen production and suggesting that some may utilise type II mechanisms of photo-sensitisation. Under dark conditions, the PhBPs examined were able to kill S. aureus with MLCs in the range 3.1 jiM to 125 MM, indicating significant levels of inherent toxicity. When illuminated, the majority of these PhBPs showed an enhanced ability to kill S. aureus with MLCs generally reduced up to the order of four-fold, clearly indicating photo-toxicity. Single cell electrophoresis (The "Comet" assay) shows that when S aureus cells are incubated with illuminated PhBPs, DNA is released from cel!s, producing long trails, which are indicative of oxidative damage to the organism's DNA, further supporting the hypothesis that DNA attack via a type II mechanism of photo-damage may be a major featured in the photo-toxic mechanism used by the PhPBs tested to kill S. aureus. The major product of DNA oxidative damage is 7,8-dihydro-8-oxo-2'-deoxyguanosine (8-oxodG) but treatment of phage A DNA with the PhBPs failed to produce an increase upon illumination, implying that the production of 8-oxodG may not generally be a major form of damage induced by the photo-toxic action of the PhBPs tested on DNA.

Name dc:type.qualificationname

msc

Level dc:type.qualificationlevel

masters

Grantor dc:publisher.institution

University of Central Lancashire

Year dc:date.issued

2003

Author dc:creator

• Sayed, Zia Ashraf

• F990 - Physical sciences not elsewhere classified

Language dc:language

en