Laverty Garry, Gorman Sean P, Gilmore Brendan F
Biomaterials, Biofilm and Infection Control Research Group, School of Pharmacy, Queens University of Belfast, Medical Biology Centre, 97 Lisburn Road, Belfast, BT9 7BL, UK.
Chem Biol Drug Des. 2015 May;85(5):645-52. doi: 10.1111/cbdd.12441. Epub 2014 Oct 23.
In this study, we report the antimicrobial planktonic and biofilm kill kinetics of ultrashort cationic lipopeptides previously demonstrated by our group to have a minimum biofilm eradication concentration (MBEC) in the microgram per mL (μg/mL) range against clinically relevant biofilm-forming micro-organisms. We compare the rate of kill for the most potent of these lipopeptides, dodecanoic (lauric) acid-conjugated C12 -Orn-Orn-Trp-Trp-NH2 against the tetrapeptide amide H-Orn-Orn-Trp-Trp-NH2 motif and the amphibian peptide Maximin-4 via a modification of the MBEC Assay(™) for Physiology & Genetics (P&G). Improved antimicrobial activity is achieved upon N-terminal lipidation of the tetrapeptide amide. Increased antimicrobial potency was demonstrated against both planktonic and biofilm forms of Gram-positive micro-organisms. We hypothesize rapid kill to be achieved by targeting of microbial membranes. Complete kill against established 24-h Gram-positive biofilms occurred within 4 h of exposure to C12 -OOWW-NH2 at MBEC values [methicillin-resistant Staphylococcus epidermidis (ATCC 35984): 15.63 μg/mL] close to the values for the planktonic minimum inhibitory concentration (MIC) [methicillin-resistant Staphylococcus epidermidis (ATCC 35984): 1.95 μg/mL]. Such rapid kill, especially against sessile biofilm forms, is indicative of a reduction in the likelihood of resistant strains developing with the potential for quicker resolution of pathogenic infection. Ultrashort antimicrobial lipopeptides have high potential as antimicrobial therapy.
在本研究中，我们报告了超短阳离子脂肽的抗微生物浮游菌和生物膜杀灭动力学，我们团队之前已证明这些脂肽对临床相关的生物膜形成微生物具有微克每毫升（μg/mL）范围内的最低生物膜根除浓度（MBEC）。我们通过对生理学与遗传学（P&G）的MBEC检测法（™）进行改进，比较了这些脂肽中最有效的十二烷酸（月桂酸）共轭C12 -Orn-Orn-Trp-Trp-NH2与四肽酰胺H-Orn-Orn-Trp-Trp-NH2基序以及两栖肽Maximin-4的杀灭速率。四肽酰胺的N端脂质化提高了抗微生物活性。对革兰氏阳性微生物的浮游菌和生物膜形式均显示出抗菌效力增强。我们假设通过靶向微生物膜可实现快速杀灭。在MBEC值[耐甲氧西林表皮葡萄球菌（ATCC 35984）：15.63 μg/mL]接近浮游菌最低抑菌浓度（MIC）值[耐甲氧西林表皮葡萄球菌（ATCC 35984）：1.95 μg/mL]的情况下，暴露于C12 -OOWW-NH2 4小时内，对已形成24小时的革兰氏阳性生物膜实现了完全杀灭。这种快速杀灭，尤其是对固着生物膜形式的杀灭，表明耐药菌株产生的可能性降低，有可能更快地解决致病性感染。超短抗微生物脂肽作为抗微生物疗法具有很高的潜力。
