Weaver Alan J, Shepard Joyce B, Wilkinson Royce A, Watkins Robert L, Walton Sarah K, Radke Amanda R, Wright Thomas J, Awel Milat B, Cooper Catherine, Erikson Elizabeth, Labib Mohamed E, Voyich Jovanka M, Teintze Martin
Department of Chemistry & Biochemistry, Montana State University, Bozeman, Montana, United States of America.
Department of Chemistry & Biochemistry, Montana State University, Bozeman, Montana, United States of America; Department of Microbiology & Immunology, Montana State University, Bozeman, Montana, United States of America.
PLoS One. 2014 May 19;9(5):e97742. doi: 10.1371/journal.pone.0097742. eCollection 2014.
This study investigated the potential antibacterial activity of three series of compounds synthesized from 12 linear and branched polyamines with 2-8 amino groups, which were substituted to produce the corresponding guanides, biguanides, or phenylguanides, against Acinetobacter baumannii, Enterococcus faecalis, Escherichia coli, Pseudomonas aeruginosa and Staphylococcus aureus. Antibacterial activity was measured for each compound by determining the minimum inhibitory concentration against the bacteria, and the toxicity towards mammalian cells was determined. The most effective compound, THAM trisphenylguanide, was studied in time-to-kill and cytoplasmic leakage assays against methicillin-resistant Staphylococcus aureus (MRSA, USA300) in comparison to chlorhexidine. Preliminary toxicity and MRSA challenge studies in mice were also conducted on this compound. THAM trisphenylguanide showed significant antibacterial activity (MIC ∼1 mg/L) and selectivity against MRSA relative to all the other bacteria examined. In time-to-kill assays it showed increased antimicrobial activity against MRSA versus chlorhexidine. It induced leakage of cytoplasmic content at concentrations that did not reduce cell viability, suggesting the mechanism of action may involve membrane disruption. Using an intraperitoneal mouse model of invasive MRSA disease, THAM trisphenylguanide reduced bacterial burden locally and in deeper tissues. This study has identified a novel guanide compound with selective microbicidal activity against Staphylococcus aureus, including a methicillin-resistant (MRSA) strain.
本研究调查了由12种含2 - 8个氨基的直链和支链多胺合成的三类化合物（分别被取代生成相应的胍、双胍或苯基胍）对鲍曼不动杆菌、粪肠球菌、大肠杆菌、铜绿假单胞菌和金黄色葡萄球菌的潜在抗菌活性。通过测定每种化合物对细菌的最低抑菌浓度来衡量其抗菌活性，并测定其对哺乳动物细胞的毒性。将最有效的化合物三（苯基胍）氨基甲烷（THAM trisphenylguanide）与洗必泰进行比较，针对耐甲氧西林金黄色葡萄球菌（MRSA，USA300）进行了杀菌时间和细胞质泄漏试验研究。还对该化合物进行了小鼠初步毒性和MRSA攻毒研究。三（苯基胍）氨基甲烷（THAM trisphenylguanide）相对于所有其他检测细菌，对MRSA显示出显著的抗菌活性（MIC约为1 mg/L）和选择性。在杀菌时间试验中，它对MRSA的抗菌活性比洗必泰更强。它在不降低细胞活力的浓度下诱导细胞质内容物泄漏，这表明其作用机制可能涉及膜破坏。使用侵袭性MRSA疾病的腹腔小鼠模型，三（苯基胍）氨基甲烷（THAM trisphenylguanide）降低了局部和深部组织中的细菌载量。本研究鉴定出一种新型胍类化合物，对金黄色葡萄球菌具有选择性杀菌活性，包括耐甲氧西林（MRSA）菌株。
