CX加強抗生素對革蘭氏陰性菌的殺菌效果之機制探討

Abstract

臨床上，目前普遍使用抗生素治療因革蘭氏陰性菌所引起的感染症，這樣的治療方法缺點在於抗生素的濫用帶來的篩選壓力，使得抗藥性細菌出現。革蘭氏陰性菌具有多重的抗藥性機制，一旦發現抗藥性菌株大多已是多重抗藥性菌株，造成後續治療上的困難。本實驗室先前研究發現，CX能有效加強光動力的殺菌效果，希望藉由CX的協助加強抗生素對革蘭氏陰性菌的殺菌效果，降低抗生素的使用量。 研究發現，CX和抗生素作用與抗生素單獨使用時相比較，發現能多降低7個log值生菌數而達全殺的效果，而且加入CX於不同抗生素的MIC濃度時，最終達到的殺菌效果顯著比使用MIC以上濃度的殺菌效果更好，因此CX可加強不同種類的抗生素對革蘭氏陰性菌之殺菌效果，同時亦能協助降低抗生素使用劑量；CX的加強殺菌效果也對抗藥性菌株有效，但CX無法加強EDTA在綠膿桿菌的殺菌效果。至於應用在綠膿桿菌的生物膜殺菌上，可能是受到胞外聚合物的阻礙使CX無法進入生物膜與細菌接觸，因此無法如同在懸浮培養上有增強殺菌的效果。未來實驗室計劃將朝向改良CX的性質與破壞生物膜表面的胞外聚合物，再觀察CX在抗生素對生物膜上的殺菌效果之影響

Antibiotics are the most popular antimicrobial agent used for the treatment of infection caused by Gram-negative bacteria. However, drug-resistance is a growing problem largely due to the widespread use of antibiotics in medicine. The opportunistic Pseudomonas aeruginosa (P. aeruginosa) is one of Gram-negative bacteria, which has been identified several drug-resistant strains in clinics. Therefore, it is necessary to develop an alternative antimicrobial technique which is effective in the treatment of multi-drug resistant bacteria infections. In the presence of compound X (CX), we have previously found that hematoporphyrin (Hp)-mediated photodynamic inactivation (PDI) could increase the bacterial killing against Gram-positive as well as Gram-negative bacteria. In this study, we further address whether CX can exert synergistic antimicrobial effect in antibiotics against Gram-negative bacteria. We found that CX can synergistically increase the antibiotics-mediated bactericidal effects. Under the MIC concentration, the bacterial effect of Polymyxin B 、 Colistin 、 Imipenem 、Gentamicin and Ciprofloxacin is around 2~3 log against P. aeruginosa in platonic culture; however, complete killing could be found in the presence of 0.25% CX. Similar results were also found in other Gram-negative bacterial, Acinetobacter baumannii。However, this synergistic effect of antibiotics and CX was not found in biofilm study, which might relate to the extracellular polymeric substances of biofilm.