Evaluations of Antibacterial and Antibiofilm Properties of Antibiotics Teixobactin

抗菌素耐药性对全球健康构成威胁，导致死亡率和发病率的增加。革兰氏阳性细菌作为生物膜在表面形成群落的能力也会导致耐药性增加，这种感染更难用目前批准的抗生素治疗。因此，需要新的有效抗生素进入药物流水线。抗菌肽是一类由多种生物产生的作为免疫应答的抗菌素，为合成化学家合成新型抗菌剂提供了新的天然产物。Teixobactin是一种大环去脂肽，具有良好的抗革兰氏阳性菌活性，对革兰氏阳性菌无耐药性，靶向脂类II和类脂III抑制细菌细胞壁的生物合成。Teixobactin由11个氨基酸组成，具有直链和大环状结构，由几个蛋白来源的氨基酸和一个非蛋白来源的氨基酸(L-别尿苷)组成。1以往的研究表明，teixobactin中的一些残基可以被修饰成不同的功能基团，从而增强或不丧失抗菌活性。2-6分析了teixobactin类似物的作用模式。7最近的研究还表明，teixobactin类似物对包括表皮葡萄球菌和金黄色葡萄球菌在内的葡萄球菌生物膜具有抗生物膜活性。8本项目的目标是合成具有新修饰的teixobactin化合物，并评价其对浮游细菌和细菌生物膜的生物活性。可以分析这些类似物更广泛的结构活性关系，以增强抗菌活性。通过对金黄色葡萄球菌等革兰氏阳性菌的最小抑菌浓度(MIC)研究，合成并筛选了替克生类似物的文库。进一步研究了有效的teixobactin类似物，以分析其对细菌生物膜的抗生物膜性能。参考文献(1)Ling，L.；Schneider，T.；People，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.；米利特，W.P.；Nitti，A.G.；Zullo，A.M.；Chen，C.；Lewis，K.一种新的抗生素杀死没有检测到耐药性的病原体。《自然》2015,517(7535)，455-459。Https://doi.org/10.1038/nature14098.(2)Parmar，A.；Iyer，A.；文森特，C.S.；Van Lysebetten，D.；Prior，S.H.；Madder，A.；Taylor，E.J.；Singh，I.两个Teixobactin类似物的有效全合成和生物活性。化学。交警。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.；文森特，C.S.；Palmai-Pallag，T.；Bachrati，C.Z.；Breukink，E.；Madder，A.；Lakshminarayanan，R.；Taylor，E.J.；Singh，I.Teixobactin类似物揭示了恩达西定对于高度有效的抗菌活性和脂质II结合不是必需的。化学。SCI。2017、8(12)、8183-8192。Https://doi.org/10.1039/C7SC03241B.(4)Parmar，A.；Prior，S.H.；Iyer，A.；文森特，C.S.；Van Lysebetten，D.；Breukink，E.；Madder，A.；Taylor，E.J.；Singh，I.定义了Teixobactin类似物的分子结构，并了解它们在抗菌活性中的作用。化学。交警。2017、53(12)、2016-2019年。Https://doi.org/10.1039/C6CC09490B.(5)Parmar，A.；Iyer，A.；Lloyd，D.G.；文森特，C.S.；Prior，S.H.；Madder，A.；Taylor，E.J.；Singh，I.通过用L-别氨基-恩杜拉地丁的异构体取代耐甲氧西林金黄色葡萄球菌(MRSA)，合成了有效对抗耐甲氧西林金黄色葡萄球菌(MRSA)的替克生类似物。化学。交警。2017年，53(55)，7788-7791。Https://doi.org/10.1039/C7CC04021K

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