Singh Pawan Kumar, Donovan David M, Kumar Ashok
Department of Ophthalmology and Kresge Eye Institute, Wayne State University, Detroit, Michigan, USA.
BARC, Agricultural Research Service, U.S. Department of Agriculture, Beltsville, Maryland, USA.
Antimicrob Agents Chemother. 2014 Aug;58(8):4621-9. doi: 10.1128/AAC.00126-14. Epub 2014 Jun 2.
The treatment of endophthalmitis is becoming very challenging due to the emergence of multidrug-resistant bacteria. Hence, the development of novel therapeutic alternatives for ocular use is essential. Here, we evaluated the therapeutic potential of Ply187AN-KSH3b, a chimeric phage endolysin derived from the Ply187 prophage, in a mouse model of Staphylococcus aureus endophthalmitis. Our data showed that the chimeric Ply187 endolysin exhibited strong antimicrobial activity against both methicillin-sensitive S. aureus and methicillin-resistant S. aureus (MRSA) strains, as evidenced by MIC determinations, reductions in turbidity, and disruption of biofilms. Moreover, exposure of S. aureus to Ply187 for up to 10 generations did not lead to resistance development. The intravitreal injection of chimeric Ply187 (at 6 or 12 h postinfection) significantly improved the outcome of endophthalmitis, preserved retinal structural integrity, and maintained visual function as assessed by electroretinogram analysis. Furthermore, phage lysin treatment significantly reduced the bacterial burden and the levels of inflammatory cytokines and neutrophil infiltration in the eyes. These results indicate that the intravitreal administration of a phage lytic enzyme attenuates the development of bacterial endophthalmitis in mice. To the best of our knowledge, this is the first study demonstrating the therapeutic use of phage-based antimicrobials in ocular infections.
由于多重耐药细菌的出现，眼内炎的治疗变得极具挑战性。因此，开发新型眼部治疗替代方案至关重要。在此，我们在金黄色葡萄球菌性眼内炎小鼠模型中评估了源自Ply187前噬菌体的嵌合噬菌体溶菌酶Ply187AN-KSH3b的治疗潜力。我们的数据表明，嵌合Ply187溶菌酶对甲氧西林敏感金黄色葡萄球菌和耐甲氧西林金黄色葡萄球菌（MRSA）菌株均表现出强大的抗菌活性，这通过最低抑菌浓度测定、浊度降低和生物膜破坏得以证明。此外，将金黄色葡萄球菌暴露于Ply187长达10代并未导致耐药性产生。玻璃体内注射嵌合Ply187（感染后6或12小时）显著改善了眼内炎的预后，保留了视网膜结构完整性，并通过视网膜电图分析评估维持了视觉功能。此外，噬菌体溶菌酶治疗显著降低了眼部的细菌载量以及炎性细胞因子水平和中性粒细胞浸润。这些结果表明，玻璃体内注射噬菌体裂解酶可减轻小鼠细菌性眼内炎的发展。据我们所知，这是第一项证明基于噬菌体的抗菌剂在眼部感染中具有治疗用途的研究。
