Mohammad Haroon, Cushman Mark, Seleem Mohamed N
Department of Comparative Pathobiology, Purdue University College of Veterinary Medicine, West Lafayette, Indiana, United States of America.
Department of Medicinal Chemistry and Molecular Pharmacology, Purdue University College of Pharmacy, and the Purdue Center for Cancer Research, West Lafayette, Indiana, United States of America.
PLoS One. 2015 Nov 4;10(11):e0142321. doi: 10.1371/journal.pone.0142321. eCollection 2015.
The emergence of community-associated methicillin-resistant Staphylococcus aureus (MRSA), including strains resistant to current antibiotics, has contributed to an increase in the number of skin infections reported in humans in recent years. New therapeutic options are needed to counter this public health challenge. The aim of the present study was to examine the potential of thiazole compounds synthesized by our research group to be used topically to treat MRSA skin and wound infections. The broth microdilution method confirmed that the lead thiazole compound and four analogues are capable of inhibiting MRSA growth at concentrations as low as 1.3 μg/mL. Additionally, three compounds exhibited a synergistic relationship when combined with the topical antibiotic mupirocin against MRSA in vitro via the checkerboard assay. Thus the thiazole compounds have potential to be used alone or in combination with mupirocin against MRSA. When tested against human keratinocytes, four derivatives of the lead compound demonstrated an improved toxicity profile (were found to be non-toxic up to a concentration of 20 μg/mL). Utilizing a murine skin infection model, we confirmed that the lead compound and three analogues exhibited potent antimicrobial activity in vivo, with similar capability as the antibiotic mupirocin, as they reduced the burden of MRSA present in skin wounds by more than 90%. Taken altogether, the present study provides important evidence that these thiazole compounds warrant further investigation for development as novel topical antimicrobials to treat MRSA skin infections.
社区获得性耐甲氧西林金黄色葡萄球菌（MRSA）的出现，包括对现有抗生素耐药的菌株，导致近年来人类报告的皮肤感染病例增多。需要新的治疗选择来应对这一公共卫生挑战。本研究的目的是检验我们研究小组合成的噻唑化合物局部用于治疗MRSA皮肤和伤口感染的潜力。肉汤微量稀释法证实，主要噻唑化合物及其四种类似物能够在低至1.3μg/mL的浓度下抑制MRSA生长。此外，通过棋盘法检测，三种化合物与局部抗生素莫匹罗星联合使用时，在体外对MRSA表现出协同关系。因此，噻唑化合物有潜力单独使用或与莫匹罗星联合用于对抗MRSA。在对人角质形成细胞进行测试时，主要化合物的四种衍生物显示出改善的毒性特征（在浓度高达20μg/mL时无毒）。利用小鼠皮肤感染模型，我们证实主要化合物及其三种类似物在体内表现出强大的抗菌活性，与抗生素莫匹罗星的能力相似，因为它们使皮肤伤口中存在的MRSA负担减少了90%以上。综上所述，本研究提供了重要证据，表明这些噻唑化合物作为治疗MRSA皮肤感染的新型局部抗菌药物值得进一步研究开发。
