Antimicrobial photodynamic therapy (aPDT) is a promising method for the topical treatment of drug-resistant staphylococcal infections and can be further improved by identifying mechanisms that increase the specificity of photosensitizer uptake by bacteria. Here we show that Ga(III)-protoporphyrin IX chloride (Ga-PpIX), a fluorescent hemin analog with previously undisclosed photosensitizing properties, can be taken up within seconds by Staphylococcus aureus including multidrug-resistant strains such as MRSA. The uptake of Ga-PpIX by staphylococci is likely diffusion-limited and is attributed to the expression of high-affinity cell-surface hemin receptors (CSHRs), namely iron-regulated surface determinant (Isd) proteins. A structure–activity study reveals the ionic character of both the heme center and propionyl groups to be important for uptake specificity. Ga-PpIX was evaluated as a photosensitizer against S. aureus and several clinical isolates of MRSA using a visible light source, with antimicrobial activity at 0.03 μM with 10 s of irradiation by a 405 nm diode array (1.4 J/cm²); antimicrobial activity could also be achieved within minutes using a compact fluorescent lightbulb. GaPpIX was not only many times more potent than PpIX, a standard photosensitizer featured in clinical aPDI, but also demonstrated low cytotoxicity against HEK293 cells and human keratinocytes. Ga-PpIX uptake was screened against a diverse panel of bacterial pathogens using a fluorescence-based imaging assay, which revealed rapid uptake by several Gram-positive species known to express CSHRs, suggesting future candidates for targeted aPDT.

中文翻译：

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Ga（III）-原卟啉IX对葡萄球菌的快速吸收和光动力学灭活

抗菌光动力疗法（aPDT）是一种用于耐药性葡萄球菌感染的局部治疗的有前途的方法，可以通过确定增加细菌摄取光敏剂特异性的机制来进一步改善。在这里我们显示，Ga（III）-原卟啉IX氯化物（Ga-PpIX），一种具有以前未公开的光敏特性的荧光血红素类似物，可以在几秒钟内被金黄色葡萄球菌吸收。包括多重耐药菌株，例如MRSA。葡萄球菌对Ga-PpIX的摄取可能受到扩散限制，并归因于高亲和力的细胞表面血红素受体（CSHRs）的表达，即铁调节的表面决定簇（Isd）蛋白。结构活性研究表明，血红素中心和丙酰基的离子特征对于摄取特异性很重要。Ga-PpIX被评估为对金黄色葡萄球菌和几种MRSA临床分离株的光敏剂，使用可见光光源，在405 nm二极管阵列（1.4 J / cm ^2）照射10 s的条件下，其抗菌活性为0.03μM。）; 使用紧凑型荧光灯灯泡也可以在数分钟内实现抗菌活性。GaPpIX的功效不仅比临床aPDI中的标准光敏剂PpIX强很多倍，而且对HEK293细胞和人角质形成细胞显示出低细胞毒性。使用基于荧光的成像分析针对多种细菌病原体筛选了Ga-PpIX摄取，该分析揭示了已知表达CSHRs的几种革兰氏阳性菌的快速摄取，表明了靶向aPDT的未来候选者。