Evaluations of Antibacterial and Antibiofilm Properties of Antibiotics Teixobactin

抗生素 Teixobactin 的抗菌和抗生物膜特性评价

• 批准号: 2490965
• 金额: --
• 依托单位: University of Liverpool
• 依托单位国家: 英国
• 项目类别: Studentship
• 财政年份: 2021
• 资助国家: 英国
• 起止时间: 2021 至 无数据
• 项目状态: 未结题
• 来源: https://gtr.ukri.org/projects?ref=studentship-2490965
• 关键词: Evaluations; Antibacterial; Antibiofilm; Properties; Antibiotics

Antimicrobial resistance (AMR) represents a threat to global health, leading to an increase in mortality and morbidity rate. The ability for Gram-positive bacteria to form communities on surfaces as biofilms also lead to increased resistance and such infections are more difficult to treat with currently approved antibiotics. Therefore, new potent antibiotics are in need to enter the drug pipeline. Antimicrobial peptides are a class of antimicrobials which are generated by many organisms as part of immune responses, which provide new natural products for synthetic chemists to synthesise novel antimicrobials. Teixobactin is a macrocyclic depsipeptide presenting excellent activity against Gram-positive bacteria without detectable resistance, targeting lipid II and III to inhibit bacterial cell wall biosynthesis. Teixobactin consists of 11 amino acids with a linear chain and macrocyclic ring, which is constituted by several proteinogenic and one non-proteinogenic amino acid (l-allo-enduracididine).1 Previous studies revealed that some residues within teixobactin can be modified to different functional groups with enhanced or no loss of antimicrobial activity.2-6 The mode of action of teixobactin analogues was analysed.7 Recent studies also revealed that teixobactin analogues exhibit antibiofilm activity against biofilms of Staphylococci species, including Staphylococcus epidermis and Staphylococcus aureus.8 The aims of current projects are to synthesise teixobactin analogues with novel modifications and evaluate their bioactive activities against planktonic bacteria and bacterial biofilms. A broader scope of structural activity relationship for these analogues can be analysed to enhance antimicrobial activity. Libraries of teixobactin analogues were synthesised and screened by minimal inhibitory concentration (MIC) studies against Gram-positive bacteria as such as Staphylococcus aureus. Potent teixobactin analogues were further studied to analyse the antibiofilm properties against bacterial biofilms. Biological data can provide information on the lead drug candidates for further in vitro and in vivo studies against Gram-positive bacteria and associated biofilms.References(1) Ling, L. L.; Schneider, T.; Peoples, A. J.; Spoering, A. L.; Engels, I.; Conlon, B. P.; Mueller, A.; Schäberle, T. F.; Hughes, D. E.; Epstein, S.; Jones, M.; Lazarides, L.; Steadman, V. A.; Cohen, D. R.; Felix, C. R.; Fetterman, K. A.; Millett, W. P.; Nitti, A. G.; Zullo, A. M.; Chen, C.; Lewis, K. A New Antibiotic Kills Pathogens without Detectable Resistance. Nature 2015, 517 (7535), 455-459. https://doi.org/10.1038/nature14098.(2) Parmar, A.; Iyer, A.; Vincent, C. S.; Van Lysebetten, D.; Prior, S. H.; Madder, A.; Taylor, E. J.; Singh, I. Efficient Total Syntheses and Biological Activities of Two Teixobactin Analogues. Chem. Commun. 2016, 52 (36), 6060-6063. https://doi.org/10.1039/C5CC10249A.(3) Parmar, A.; Iyer, A.; Prior, S. H.; Lloyd, D. G.; Leng Goh, E. T.; Vincent, C. S.; Palmai-Pallag, T.; Bachrati, C. Z.; Breukink, E.; Madder, A.; Lakshminarayanan, R.; Taylor, E. J.; Singh, I. Teixobactin Analogues Reveal Enduracididine to Be Non-Essential for Highly Potent Antibacterial Activity and Lipid II Binding. Chem. Sci. 2017, 8 (12), 8183-8192. https://doi.org/10.1039/C7SC03241B.(4) Parmar, A.; Prior, S. H.; Iyer, A.; Vincent, C. S.; Van Lysebetten, D.; Breukink, E.; Madder, A.; Taylor, E. J.; Singh, I. Defining the Molecular Structure of Teixobactin Analogues and Understanding Their Role in Antibacterial Activities. Chem. Commun. 2017, 53 (12), 2016-2019. https://doi.org/10.1039/C6CC09490B.(5) Parmar, A.; Iyer, A.; Lloyd, D. G.; Vincent, C. S.; Prior, S. H.; Madder, A.; Taylor, E. J.; Singh, I. Syntheses of Potent Teixobactin Analogues against Methicillin-Resistant Staphylococcus Aureus (MRSA) through the Replacement of l-Allo-Enduracididine with Its Isosteres. Chem. Commun. 2017, 53 (55), 7788-7791. https://doi.org/10.1039/C7CC04021K

抗生素耐药性（AMR）是对全球健康的威胁，导致死亡率和发病率增加。革兰氏阳性菌在表面上形成生物膜群落的能力也会导致耐药性增加，并且这种感染更难以用目前批准的抗生素治疗。因此，需要新的强效抗生素进入药物管道。抗菌肽是一类由许多生物体产生的作为免疫应答的一部分的抗菌剂，其为合成化学家合成新型抗菌剂提供了新的天然产物。Teixobactin是一种大环缩酚酸肽，对革兰氏阳性菌具有优异的活性，没有可检测到的耐药性，靶向脂质II和III以抑制细菌细胞壁生物合成。Teixobactin由11个具有直链和大环的氨基酸组成，其由几种蛋白质氨基酸和一种非蛋白质氨基酸构成（l-别洛-阿托西啶）。1先前的研究表明，替沙菌素中的一些残基可以被修饰为不同的官能团，从而增强或不丧失抗微生物活性。2- 6分析了teixobactin类似物的作用模式。7最近的研究还表明，teixobactin类似物对葡萄球菌属物种的生物膜表现出抗生物膜活性，包括表皮葡萄球菌和金黄色葡萄球菌。8目前项目的目的是合成具有新修饰的teixobactin类似物，并评估其对嗜酸细菌和细菌生物膜的生物活性。可以分析这些类似物的更广泛的结构活性关系以增强抗微生物活性。合成了替沙菌素类似物的文库，并通过针对革兰氏阳性细菌如金黄色葡萄球菌的最小抑菌浓度（MIC）研究进行筛选。进一步研究了有效的teixobactin类似物，以分析抗细菌生物膜的生物膜特性。生物学数据可以提供关于先导药物候选物的信息，用于针对革兰氏阳性菌和相关生物膜的进一步体外和体内研究。L.的; Schneider，T.; Peoples，A. J.道：Spoering，A. L.的; Engels，I.;康伦，B。P的; Mueller，A.; Schäberle，T. F.地;休斯，D. E.的; Epstein，S.; Jones，M.; Lazarides，L.; Steadman，V. A.;科恩，D.的R.;费利克斯角的R.; Fetterman，K.一、Millett，W. P的; Nitti，A. G.地; Zullo，A. M.; Chen，C.;刘易斯，K.一种新的抗生素杀死病原体而没有检测到耐药性。Nature 2015，517（7535），455-459. https://doi.org/10.1038/nature14098. (2)Parmar，A.; Iyer，A.;文森特角S.的;货车Lysebetten，D.; Prior，S. H.的; Madder，A.; Taylor，E. J.道：辛格岛两个Teixobactin类似物的高效全合成及其生物活性。化学通信2016，52（36），6060-6063. https://doi.org/10.1039/C5CC10249A. (3)Parmar，A.; Iyer，A.; Prior，S. H.的;劳埃德，D。G.地; Leng Goh，E. T.;文森特角S.的; Palmai-Pallag，T.;巴赫拉蒂角Z.的; Breukink，E.; Madder，A.; Lakshminarayanan，R.;泰勒，E. J.道：辛格岛Teixobactin类似物揭示Enduracididine对于高效抗菌活性和脂质II结合不是必需的。化学科学2017，8（12），8183-8192. https://doi.org/10.1039/C7SC03241B. (4)Parmar，A.; Prior，S. H.的; Iyer，A.;文森特角S.的;货车Lysebetten，D.; Breukink，E.; Madder，A.; Taylor，E. J.道：辛格岛定义Teixobactin类似物的分子结构并了解其在抗菌活性中的作用。化学通信2017，53（12），2016-2019。https://doi.org/10.1039/C6CC09490B. (5)Parmar，A.; Iyer，A.;劳埃德，D。G.地;文森特角S.的; Prior，S. H.的; Madder，A.; Taylor，E. J.道：辛格岛通过用其电子等排体替代l-异源-Enduracididine合成有效的抗甲氧西林耐药金黄色葡萄球菌（MRSA）的Teixobactin类似物。化学通信2017，53（55），7788-7791. https://doi.org/10.1039/C7CC04021K