Cationic Amphiphiles, a New Generation of Antimicrobials Inspired by the Natural Antimicrobial Peptide Scaffold

Antimicrobial Agents and Chemotherapy - Tập 54 Số 10 - Trang 4049-4058 - 2010
Brandon Findlay1, George G. Zhanel2, Frank Schweizer1,2
1Department of Chemistry, University of Manitoba Winnipeg, Manitoba R3T 2N2 Canada
2Department of Medical Microbiology, University of Manitoba, Winnipeg, Manitoba R3A 1R9, Canada

Tóm tắt

ABSTRACT Naturally occurring cationic antimicrobial peptides (AMPs) and their mimics form a diverse class of antibacterial agents currently validated in preclinical and clinical settings for the treatment of infections caused by antimicrobial-resistant bacteria. Numerous studies with linear, cyclic, and diastereomeric AMPs have strongly supported the hypothesis that their physicochemical properties, rather than any specific amino acid sequence, are responsible for their microbiological activities. It is generally believed that the amphiphilic topology is essential for insertion into and disruption of the cytoplasmic membrane. In particular, the ability to rapidly kill bacteria and the relative difficulty with which bacteria develop resistance make AMPs and their mimics attractive targets for drug development. However, the therapeutic use of naturally occurring AMPs is hampered by the high manufacturing costs, poor pharmacokinetic properties, and low bacteriological efficacy in animal models. In order to overcome these problems, a variety of novel and structurally diverse cationic amphiphiles that mimic the amphiphilic topology of AMPs have recently appeared. Many of these compounds exhibit superior pharmacokinetic properties and reduced in vitro toxicity while retaining potent antibacterial activity against resistant and nonresistant bacteria. In summary, cationic amphiphiles promise to provide a new and rich source of diverse antibacterial lead structures in the years to come.

Từ khóa


Tài liệu tham khảo

10.1021/bm800569x

10.1021/bi011549t

10.1021/jm900615h

10.1128/AAC.00208-07

10.1021/jm800345u

10.1021/jm1000437

10.1093/jac/dkq083

10.1016/j.bmcl.2010.03.116

10.1002/chem.200802635

10.1128/AAC.48.8.3127-3129.2004

10.1038/nrmicro1098

10.1128/AAC.00925-06

10.1074/jbc.M413406200

10.1111/j.1747-0285.2006.00349.x

10.1073/pnas.0811818106

10.1007/978-1-60761-594-1_12

10.1016/S0005-2736(99)00201-1

10.1021/jm800495u

10.1021/jm8015365

10.1093/jac/dkn464

10.1021/bm800855t

10.1128/AAC.43.4.782

10.1016/j.bmc.2006.06.027

10.1007/978-1-60761-594-1_10

10.1586/14787210.5.6.951

10.1038/nbt1267

10.1073/pnas.97.16.8856

10.1016/j.mce.2006.06.017

10.1021/jm701600a

10.1074/jbc.M709154200

10.1038/nbt1113

10.1021/bm8000765

10.1128/CMR.00056-05

10.1002/bip.20911

10.1021/bi802127h

10.1016/0022-2836(82)90515-0

10.1128/AAC.00828-06

10.1002/cbic.200700502

10.1021/la802953v

10.1021/bi8011675

10.1021/bi0502386

10.1042/BJ20050520

10.1016/j.coph.2006.04.006

10.1016/j.bbamem.2008.09.013

10.1038/nrmicro2095

10.1021/ja075373f

10.1039/b815368j

10.1021/ja077288d

10.1503/cmaj.080239

10.1002/anie.200503567

10.1016/S1473-3099(06)70636-3

10.1021/bi049944h

10.1006/bbrc.1998.8159

10.1098/rspb.2005.3301

10.1038/nrmicro1441

10.1016/S0140-6736(02)11201-3

10.1016/j.chembiol.2008.03.006

10.1038/nbt1309

10.1016/j.bbamem.2008.10.020

10.1096/fj.07-105015

10.1128/AAC.00656-08

10.1126/science.1185723

10.1016/j.copbio.2008.10.013

10.1128/AAC.01100-08

10.1016/S0196-9781(01)00498-3

10.1016/S0924-8579(09)70004-4

10.1039/b719950c

10.1021/jm0340039

10.1021/bi7019904

10.1016/j.chembiol.2006.02.007

10.1073/pnas.082046199

10.1128/AAC.00526-08

10.1074/jbc.M805171200

10.1093/nar/gkn823

10.1196/annals.1326.030

10.1111/j.1365-2672.2008.03942.x

10.1073/pnas.0806456105

10.1056/NEJMe020106

10.1021/jm800997s

10.1038/ja.2009.66

10.1016/j.bbrc.2006.08.094

10.1111/j.1747-0285.2008.00769.x

10.1016/j.bbamem.2007.03.010

Thông tin
Thông tin xuất bản

Antimicrobial Agents and Chemotherapy

Tập 54 Số 10

4049-4058

Thông tin tác giả