Abstract

Due to a high unresponsiveness to chemotherapy, biofilm formation is an important medical problem that frequently occurs during infection with many bacterial pathogens. In this study, the marine sponge-derived natural compounds 4,6-dibromo-2-(2′,4′-dibromophenoxy)phenol and 3,4,6-tribromo-2-(2′,4′-dibromophenoxy)phenol were found to exhibit broad antibacterial activity against medically relevant gram-positive and gram-negative pathogens. The compounds were not only bactericidal against both replicating and stationary phase–persistent planktonic cells of methicillin-resistant Staphylococcus aureus (MRSA) and Pseudomonas aeruginosa; they also killed biofilm-incorporated cells of both species while not affecting biofilm structural integrity. Moreover, these compounds were active against carbapenemase-producing Enterobacter sp. This simultaneous activity of compounds against different growth forms of both gram-positive and gram-negative bacteria is rare. Genome sequencing of spontaneous resistant mutants and proteome analysis suggest that resistance is mediated by downregulation of the bacterial EIIBC phosphotransferase components scrA and mtlA in MRSA likely leading to a lower uptake of the molecules. Due to their only moderate cytotoxicity against human cell lines, phenoxyphenols provide an interesting new scaffold for development of antimicrobial agents with activity against planktonic cells, persisters and biofilm-incoporated cells of ESKAPE pathogens.

Key points

• Brominated phenoxyphenols kill actively replicating and biofilm-incorporated bacteria.

• Phosphotransferase systems mediate uptake of brominated phenoxyphenols.

• Downregulation of phosphotransferase systems mediate resistance.

中文翻译：

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天然溴化苯氧酚会杀死MRSA和其他病原细菌的持久性和生物膜结合细胞。

摘要

由于对化学疗法的高度无反应性，生物膜形成是一个重要的医学问题，在许多细菌性病原体感染期间经常发生。在这项研究中，海洋海绵衍生的天然化合物4,6-二溴-2-（2'，4'-二溴苯氧基）苯酚和3,4,6-三溴-2-（2'，4'-二溴苯氧基）苯酚被发现对医学相关的革兰氏阳性和革兰氏阴性病原体表现出广泛的抗菌活性。这些化合物不仅对耐甲氧西林的金黄色葡萄球菌（MRSA）和铜绿假单胞菌的复制和静止期持久性浮游细胞都有杀菌作用。; 他们还杀死了两个物种的生物膜结合细胞，同时不影响生物膜的结构完整性。而且，这些化合物对产生碳青霉烯酶的肠杆菌属细菌具有活性。化合物对革兰氏阳性和革兰氏阴性细菌的不同生长形式的这种同时活性很少见。自发抗性突变体的基因组测序和蛋白质组分析表明抗性是由细菌EIIBC磷酸转移酶组分scrA和mtlA的下调介导的在MRSA中可能会导致较低的分子摄取。由于苯酚仅对人细胞系具有中等程度的细胞毒性，因此苯酚为抗微生物剂的开发提供了有趣的新支架，该抗微生物剂具有抗ESKAPE病原体的浮游细胞，滞留剂和生物膜渗透细胞的活性。

关键点

•溴化苯氧酚会杀死活跃复制的生物膜结合细菌。

•磷酸转移酶系统介导溴化苯氧酚的吸收。

•磷酸转移酶系统的下调介导了抗性。